Compositions comprising ephedrine or an ephedrine salt and methods of making and using same

ABSTRACT

The present disclosure provides compositions comprising ephedrine sulfate ready for immediate use in a clinical setting, and methods of making and using same.

PRIORITY CLAIM

This application is a continuation application of U.S. patentapplication Ser. No. 17/381,770, filed Jul. 21, 2021, which is acontinuation application of U.S. patent application Ser. No. 16/876,020,filed May 16, 2020, and now issued as U.S. Pat. No. 11,090,278, whichclaims priority to U.S. Provisional Patent Application Ser. No.62/849,125, filed May 16, 2019, the entire contents of each of which areincorporated herein by reference and relied upon.

BACKGROUND

Ephedrine sulfate ((1R,2S)-(−)-2-methylamine-1-phenylpropan-1-olsulfate) is an alpha- and beta-adrenergic agonist and anorepinephrine-releasing agent that is FDA-approved for the treatment ofclinically important hypotension occurring in the setting of anesthesia.However, all FDA-approved formulations must be diluted ten-fold beforeadministration to a patient. Requiring dilution steps is inconvenient,delays administration of needed therapeutic intervention, and introducesa significant and dangerous source of potential error in the clinicalsetting. Dilution just before administration also introduces asignificant risk of contamination to an otherwise sterile composition.For example, a recent study by the Institute for Safe Medicine Practicesrevealed that nearly 1 in 10 drug products are prepared incorrectlybefore dispensing to a patient. A 2009 survey reported that 30% ofhospitals reported a patient event involving a compounding error in theprevious 5-year period.

Shelf-stable ready-to-use formulations commonly include excipients, suchas preservatives and/or chelating agents. The use of such agents, whileadvantageous from a stability perspective, prevents broad use ofprediluted compositions due to risks of allergic reactions, patientsensitivities, and undesirable cross-reactivities with othermedications. These risks are significant in certain settings, such asthe emergency room, where quick action is required, often in the absenceof complete patient records.

Typically, ephedrine sulfate compositions are prepared using asepticcompounding techniques, whether by a compounding lab or on-site by amedical professional. While generally considered to be safe, asepticcompounding still results in frequent (circa 1/1,000) contamination bybiological materials. For example, Sandoz, US Compounding, PharmakonPharmaceuticals, Allergy Laboratories, Cantrell Drug Company, SCAPharmaceuticals, Banner Pharmaceuticals and PherMEDium have recalleddozens of lots of compounded ephedrine sulfate, representing severalmillion doses, for lack of sterility assurance since 2012. Currentmethods of administering ephedrine sulfate compositions therefore carrya serious infection risk to patients.

Ephedrine sulfate compositions are known to be susceptible to light, pHchanges, and humidity. FDA-approved formulations have short shelf lives,typically about 24 months. Ready-to-use (e.g., prediluted) preparationsof ephedrine sulfate are not known to be stable for more than 60 days;ready-to-use formulations of other ephedrine salts are not known to bestable for more than 12 months.

In view of these clinically relevant shortcomings, a need exists forimproved formulations of ephedrine sulfate.

SUMMARY

The present disclosure provides formulations comprising ephedrinesulfate.

In some embodiments, the present disclosure provides compositionscomprising ephedrine sulfate in water, wherein the ephedrine sulfate ispresent at a concentration of about 1 mg/mL to about 10 mg/mL.

In other embodiments, the present disclosure provides a sterileprediluted medicament comprising about 3.8 mg/mL of ephedrine or anequimolar amount of an ephedrine salt; about 9 mg/mL sodium chloride;and water.

In other embodiments, the present disclosure provides a packagedpharmaceutical product comprising a vial; and a solution housed withinthe vial, wherein the solution comprises, consists essentially of, orconsists of about 5 mg/mL of ephedrine sulfate; about 9 mg/mL sodiumchloride; and water.

In other embodiments, the present disclosure provides a method ofadministering ephedrine sulfate to a subject in need thereof, the methodcomprising drawing a composition comprising ephedrine sulfate from asterile premixed pharmaceutical product into a syringe; and injectingthe composition into the subject using the syringe, wherein theephedrine sulfate is present in the composition in an amount of about 5mg/mL.

In other embodiments, the present disclosure provides a method of makinga ready-to-use pharmaceutical composition comprising ephedrine or anephedrine salt, the method comprising combining ephedrine or anephedrine salt, sodium chloride and water to provide a solutioncomprising about 3.8 mg/mL ephedrine or an equimolar amount of anephedrine salt, and about 9 mg/mL sodium chloride; and thereaftersterilizing the solution to provide a ready-to-use pharmaceuticalcomposition comprising ephedrine or an ephedrine salt.

These and other embodiments are described in further detail hereinbelow.

The detailed description and examples provided herewith depict variousembodiments of this disclosure for purposes of illustration only. Oneskilled in the art will readily recognize from the following discussionthat alternative embodiments of the structures and methods illustratedherein may be employed without departing from the principles ofembodiments described herein.

DETAILED DESCRIPTION

The present disclosure provides compositions (e.g., ready-to-usepremixed pharmaceutical compositions) comprising ephedrine or anephedrine salt that are ready for immediate use in a clinical setting.

The present disclosure is based in part on the inventor's discovery thatpharmaceutical compositions consistent with those disclosed herein andcomprising an ephedrine salt (e.g., ephedrine sulfate) in a premixed(e.g., ready-to-use) formulation that does not require reconstitution ordilution prior to administration to a subject remains stable and activeafter prolonged storage.

Ephedrine and Ephedrine Salts

Compositions of the present disclosure comprise ephedrine or abiologically active salt thereof.

Ephedrine has an empirical formula of C₁₀H₁₅NO, a molecular weight of165.2 g/mol and a structural formula, in its clinically important 1R,2Senantiomer, as shown below:

Ephedrine sulfate has an empirical formula of C₂₀H₃₂N₂O₆S, a molecularweight of 428.5 g/mol and a structural formula, in its clinicallyimportant 1R,2S enantiomer, as shown below:

Ephedrine hydrochloride has an empirical formula of C₁₀H₁₆NOCl, amolecular weight of 201.7 g/mol and a structural formula, in itsclinically important 1R,2S enantiomer, as shown below:

Ephedrine and its salts feature at least two chemically reactivecenters, namely a secondary amine at C-2 and a secondary alcohol at C-1.In addition, ephedrine compositions are known to degrade during storagein a transparent container, including when contacted by light.

In some embodiments, a composition of the present disclosure comprisesephedrine. In some embodiments, the ephedrine is enantiopure(−)-ephedrine or substantially enantiopure (−)-ephedrine.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine or substantially enantiopure (−)-ephedrine atabout 20° C. for at least 12 months, the composition comprises not morethan about 30 wt. % (+)-ephedrine, for example not more than about 30wt. %, not more than about 29 wt. %, not more than about 28 wt. %, notmore than about 27 wt. %, not more than about 26 wt. %, not more thanabout 25 wt. %, not more than about 24 wt. %, not more than about 23 wt.%, not more than about 22 wt. %, not more than about 21 wt. %, not morethan about 20 wt. %, not more than about 19 wt. %, not more than about18 wt. %, not more than about 17 wt. %, not more than about 16 wt. %,not more than about 15 wt. %, not more than about 14 wt. %, not morethan about 13 wt. %, not more than about 12 wt. %, not more than about11 wt. %, not more than about 10 wt. %, not more than about 9 wt. %, notmore than about 8 wt. %, not more than about 7 wt. %, not more thanabout 6 wt. %, not more than about 5 wt. %, not more than about 4 wt. %,not more than about 3 wt. %, not more than about 2 wt. %, not more thanabout 1 wt. % (+)-ephedrine.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine or substantially enantiopure (−)-ephedrine atabout 20° C. for at least 24 months, the composition comprises not morethan about 30 wt. % (+)-ephedrine, for example not more than about 30wt. %, not more than about 29 wt. %, not more than about 28 wt. %, notmore than about 27 wt. %, not more than about 26 wt. %, not more thanabout 25 wt. %, not more than about 24 wt. %, not more than about 23 wt.%, not more than about 22 wt. %, not more than about 21 wt. %, not morethan about 20 wt. %, not more than about 19 wt. %, not more than about18 wt. %, not more than about 17 wt. %, not more than about 16 wt. %,not more than about 15 wt. %, not more than about 14 wt. %, not morethan about 13 wt. %, not more than about 12 wt. %, not more than about11 wt. %, not more than about 10 wt. %, not more than about 9 wt. %, notmore than about 8 wt. %, not more than about 7 wt. %, not more thanabout 6 wt. %, not more than about 5 wt. %, not more than about 4 wt. %,not more than about 3 wt. %, not more than about 2 wt. %, not more thanabout 1 wt. % (+)-ephedrine.

In some embodiments, a composition of the present disclosure comprisesephedrine sulfate. In some embodiments, the ephedrine sulfate isenantiopure (−)-ephedrine sulfate or substantially enantiopure(−)-ephedrine sulfate.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine sulfate or substantially enantiopure(−)-ephedrine sulfate at about 20° C. for at least 12 months, thecomposition comprises not more than about 30 wt. % (+)-ephedrine or saltthereof, for example not more than about 30 wt. %, not more than about29 wt. %, not more than about 28 wt. %, not more than about 27 wt. %,not more than about 26 wt. %, not more than about 25 wt. %, not morethan about 24 wt. %, not more than about 23 wt. %, not more than about22 wt. %, not more than about 21 wt. %, not more than about 20 wt. %,not more than about 19 wt. %, not more than about 18 wt. %, not morethan about 17 wt. %, not more than about 16 wt. %, not more than about15 wt. %, not more than about 14 wt. %, not more than about 13 wt. %,not more than about 12 wt. %, not more than about 11 wt. %, not morethan about 10 wt. %, not more than about 9 wt. %, not more than about 8wt. %, not more than about 7 wt. %, not more than about 6 wt. %, notmore than about 5 wt. %, not more than about 4 wt. %, not more thanabout 3 wt. %, not more than about 2 wt. %, not more than about 1 wt. %(+)-ephedrine or salt thereof.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine sulfate or substantially enantiopure(−)-ephedrine sulfate at about 20° C. for at least 24 months, thecomposition comprises not more than about 30 wt. % (+)-ephedrine or saltthereof, for example not more than about 30 wt. %, not more than about29 wt. %, not more than about 28 wt. %, not more than about 27 wt. %,not more than about 26 wt. %, not more than about 25 wt. %, not morethan about 24 wt. %, not more than about 23 wt. %, not more than about22 wt. %, not more than about 21 wt. %, not more than about 20 wt. %,not more than about 19 wt. %, not more than about 18 wt. %, not morethan about 17 wt. %, not more than about 16 wt. %, not more than about15 wt. %, not more than about 14 wt. %, not more than about 13 wt. %,not more than about 12 wt. %, not more than about 11 wt. %, not morethan about 10 wt. %, not more than about 9 wt. %, not more than about 8wt. %, not more than about 7 wt. %, not more than about 6 wt. %, notmore than about 5 wt. %, not more than about 4 wt. %, not more thanabout 3 wt. %, not more than about 2 wt. %, not more than about 1 wt. %(+)-ephedrine or salt thereof.

In some embodiments, a composition of the present disclosure comprisesephedrine hydrochloride. In some embodiments, the ephedrinehydrochloride is enantiopure (−)-ephedrine hydrochloride orsubstantially enantiopure (−)-ephedrine hydrochloride.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine hydrochloride or substantially enantiopure(−)-ephedrine hydrochloride at about 20° C. for at least 12 months, thecomposition comprises not more than about 30 wt. % (+)-ephedrine or saltthereof, for example not more than about 30 wt. %, not more than about29 wt. %, not more than about 28 wt. %, not more than about 27 wt. %,not more than about 26 wt. %, not more than about 25 wt. %, not morethan about 24 wt. %, not more than about 23 wt. %, not more than about22 wt. %, not more than about 21 wt. %, not more than about 20 wt. %,not more than about 19 wt. %, not more than about 18 wt. %, not morethan about 17 wt. %, not more than about 16 wt. %, not more than about15 wt. %, not more than about 14 wt. %, not more than about 13 wt. %,not more than about 12 wt. %, not more than about 11 wt. %, not morethan about 10 wt. %, not more than about 9 wt. %, not more than about 8wt. %, not more than about 7 wt. %, not more than about 6 wt. %, notmore than about 5 wt. %, not more than about 4 wt. %, not more thanabout 3 wt. %, not more than about 2 wt. %, not more than about 1 wt. %(+)-ephedrine or salt thereof.

In some embodiments, after storage of a composition comprisingenantiopure (−)-ephedrine hydrochloride or substantially enantiopure(−)-ephedrine hydrochloride at about 20° C. for at least 24 months, thecomposition comprises not more than about 30 wt. % (+)-ephedrine or saltthereof, for example not more than about 30 wt. %, not more than about29 wt. %, not more than about 28 wt. %, not more than about 27 wt. %,not more than about 26 wt. %, not more than about 25 wt. %, not morethan about 24 wt. %, not more than about 23 wt. %, not more than about22 wt. %, not more than about 21 wt. %, not more than about 20 wt. %,not more than about 19 wt. %, not more than about 18 wt. %, not morethan about 17 wt. %, not more than about 16 wt. %, not more than about15 wt. %, not more than about 14 wt. %, not more than about 13 wt. %,not more than about 12 wt. %, not more than about 11 wt. %, not morethan about 10 wt. %, not more than about 9 wt. %, not more than about 8wt. %, not more than about 7 wt. %, not more than about 6 wt. %, notmore than about 5 wt. %, not more than about 4 wt. %, not more thanabout 3 wt. %, not more than about 2 wt. %, not more than about 1 wt. %(+)-ephedrine or salt thereof.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine after storageat about 20° C. for at least about 12 months, for example at least about12 months, at least about 14 months, at least about 16 months, at leastabout 18 months, at least about 20 months, at least about 22 months, atleast about 24 months, at least about 26 months, at least about 28months, at least about 30 months, at least about 32 months, at leastabout 34 months, at least about 36 months, at least about 38 months, atleast about 40 months, at least about 42 months, at least about 44months, at least about 46 months, at least about 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine after storageat about 20° C. for at least about 12 months, for example at least about12 months, at least about 14 months, at least about 16 months, at leastabout 18 months, at least about 20 months, at least about 22 months, atleast about 24 months, at least about 26 months, at least about 28months, at least about 30 months, at least about 32 months, at leastabout 34 months, at least about 36 months, at least about 38 months, atleast about 40 months, at least about 42 months, at least about 44months, at least about 46 months, at least about 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine after storageat about 20° C. for at least about 12 months, for example at least about12 months, at least about 14 months, at least about 16 months, at leastabout 18 months, at least about 20 months, at least about 22 months, atleast about 24 months, at least about 26 months, at least about 28months, at least about 30 months, at least about 32 months, at leastabout 34 months, at least about 36 months, at least about 38 months, atleast about 40 months, at least about 42 months, at least about 44months, at least about 46 months, at least about 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine after storageat about 20° C. for at least about 12 months, for example at least about12 months, at least about 14 months, at least about 16 months, at leastabout 18 months, at least about 20 months, at least about 22 months, atleast about 24 months, at least about 26 months, at least about 28months, at least about 30 months, at least about 32 months, at leastabout 34 months, at least about 36 months, at least about 38 months, atleast about 40 months, at least about 42 months, at least about 44months, at least about 46 months, at least about 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine sulfate afterstorage at about 20° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine sulfate afterstorage at about 20° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine sulfate afterstorage at about 20° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine sulfate afterstorage at about 20° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 20° C. for at least about 12 months, for exampleat least about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 20° C. for at least about 12 months, for exampleat least about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 20° C. for at least about 12 months, for exampleat least about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 20° C. for at least about 12 months, for exampleat least about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine after storageat about 40° C.+/−2° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine after storageat about 40° C.+/−2° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine after storageat about 40° C.+/−2° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine after storageat about 40° C.+/−2° C. for at least about 12 months, for example atleast about 12 months, at least about 14 months, at least about 16months, at least about 18 months, at least about 20 months, at leastabout 22 months, at least about 24 months, at least about 26 months, atleast about 28 months, at least about 30 months, at least about 32months, at least about 34 months, at least about 36 months, at leastabout 38 months, at least about 40 months, at least about 42 months, atleast about 44 months, at least about 46 months, at least about 48months.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine sulfate afterstorage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine sulfate afterstorage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine sulfate afterstorage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine sulfate afterstorage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 70% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 80% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 90% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure comprisesat least about 95% of the initial amount of (−)-ephedrine hydrochlorideafter storage at about 40° C.+/−2° C. for at least about 12 months, forexample at least about 12 months, at least about 14 months, at leastabout 16 months, at least about 18 months, at least about 20 months, atleast about 22 months, at least about 24 months, at least about 26months, at least about 28 months, at least about 30 months, at leastabout 32 months, at least about 34 months, at least about 36 months, atleast about 38 months, at least about 40 months, at least about 42months, at least about 44 months, at least about 46 months, at leastabout 48 months.

In some embodiments, a composition of the present disclosure includesnot more than about 2 μg/mL of dichlorobenzoic acid after storage atabout 25° C.+/−2° C. for at least about 12 months, for example not morethan about 2 μg/mL, not more than about 1.9 μg/mL, not more than about1.8 μg/mL, not more than about 1.7 μg/mL, not more than about 1.6 μg/mL,not more than about 1.5 μg/mL, not more than about 1.4 μg/mL, not morethan about 1.3 μg/mL, not more than about 1.2 μg/mL, not more than about1.1 μg/mL, not more than about 1 μg/mL, not more than about 0.9 μg/mL,not more than about 0.8 μg/mL, not more than about 0.7 μg/mL, not morethan about 0.6 μg/mL, not more than about 0.5 μg/mL, not more than about0.4 μg/mL, not more than about 0.3 μg/mL, not more than about 0.2 μg/mL,or not more than about 0.1 μg/mL.

In some embodiments, a composition of the present disclosure includesnot more than about 2 μg/mL of dichlorobenzoic acid after storage atabout 25° C.+/−2° C. for at least about 24 months, for example not morethan about 2 μg/mL, not more than about 1.9 μg/mL, not more than about1.8 μg/mL, not more than about 1.7 μg/mL, not more than about 1.6 μg/mL,not more than about 1.5 μg/mL, not more than about 1.4 μg/mL, not morethan about 1.3 μg/mL, not more than about 1.2 μg/mL, not more than about1.1 μg/mL, not more than about 1 μg/mL, not more than about 0.9 μg/mL,not more than about 0.8 μg/mL, not more than about 0.7 μg/mL, not morethan about 0.6 μg/mL, not more than about 0.5 μg/mL, not more than about0.4 μg/mL, not more than about 0.3 μg/mL, not more than about 0.2 μg/mL,or not more than about 0.1 μg/mL.

Ready-to-Use Ephedrine Formulations

In some embodiments, a composition of the present disclosure comprisesephedrine or an ephedrine salt, an isotonic agent, and water.

In some embodiments, a composition of the present disclosure does notinclude a preservative. Non-limiting examples of preservatives include(e.g., benzyl alcohol, chlorobutanol, phenyl ethyl alcohol), parabens(e.g., methylparaben, ethylparaben, propylparaben, butylparaben),phenols (e.g., phenol, chlorocresol, o-phenyl phenol), mercurialcompounds (e.g., thiomersal, nitromersol, phenylmercuric nitrate,phenylmercuric acetate), and quaternary ammonium compounds (e.g.,benzalkonium chloride, cetyl pyridinium chloride). In some embodiments,the composition does not include benzyl alcohol.

In some embodiments, a composition of the present disclosure does notinclude a chelating agent. Non-limiting examples of chelating agentsinclude EDTA, calcium disodium edetate, and disodium edetate. In someembodiments, the composition does not include EDTA.

In some embodiments, the composition does not include a preservative ora chelating agent. In some embodiments, the composition does not includebenzyl alcohol or EDTA.

In some embodiments, the ephedrine or ephedrine salt is present in anamount equivalent to about 3.8 mg/mL of ephedrine free base. For exampleand without limitation, embodiments in which the ephedrine or theephedrine salt consists of ephedrine free base, the ephedrine free basemay be present in an amount of about 3.8 mg/mL. In embodiments whereinthe ephedrine or the ephedrine salt consists of ephedrine sulfate, theephedrine sulfate may be present in an amount of about 5 mg/mL. Inembodiments wherein the ephedrine or the ephedrine salt consists ofephedrine hydrochloride, the ephedrine hydrochloride may be present inan amount of about 4.6 mg/mL.

In some embodiments, the isotonic agent is sodium chloride. In otherembodiments, the isotonic agent is dextrose. In embodiments in which theisotonic agent is sodium chloride, the sodium chloride may be present inan isotonic amount, such as about 9 mg/mL. In embodiments in which theisotonic agent is dextrose, the sodium chloride may be present in anisotonic amount, such as about 5%.

In some embodiments, a composition of the present disclosure comprisesephedrine (e.g., (−)-ephedrine), sodium chloride and water (e.g., waterfor injection). In some embodiments, the ephedrine is present in anamount of about 3.8 mg/mL, and the sodium chloride is present in anamount of about 9 mg/mL.

In some embodiments, a composition of the present disclosure comprisesephedrine sulfate (e.g., (−)-ephedrine sulfate), sodium chloride andwater (e.g., water for injection). In some embodiments, the ephedrinesulfate is present in an amount of about 5 mg/mL, and the sodiumchloride is present in an amount of about 9 mg/mL.

In some embodiments, a composition of the present disclosure comprisesephedrine hydrochloride (e.g., (−)-ephedrine hydrochloride), sodiumchloride and water (e.g., water for injection). In some embodiments, theephedrine hydrochloride is present in an amount of about 4.6 mg/mL, andthe sodium chloride is present in an amount of about 9 mg/mL.

In some embodiments, a composition of the present disclosure comprisesephedrine (e.g., (−)-ephedrine), dextrose and water (e.g., water forinjection). In some embodiments, the ephedrine is present in an amountof about 3.8 mg/mL, and the dextrose is present in an amount of about5%.

In some embodiments, a composition of the present disclosure comprisesephedrine sulfate (e.g., (−)-ephedrine sulfate), dextrose and water(e.g., water for injection). In some embodiments, the ephedrine sulfateis present in an amount of about 5 mg/mL, and the dextrose is present inan amount of about 5%.

In some embodiments, a composition of the present disclosure comprisesephedrine hydrochloride (e.g., (−)-ephedrine hydrochloride), dextroseand water (e.g., water for injection). In some embodiments, theephedrine hydrochloride is present in an amount of about 4.6 mg/mL, andthe dextrose is present in an amount of about 5%.

In any embodiment disclosed herein, the composition may have a totalvolume sufficient to provide an efficacious dose of ephedrine to asubject. In some embodiments, the total volume is about 5 mL to about 25mL, for example about 5 mL, about 10 mL, about 15 mL, about 20 mL, orabout 25 mL. In some embodiments, the total volume is about 10 mL.

In any embodiment disclosed herein, the composition may be housed withina container, such as a single-use container. In some embodiments, thesingle-use container is a vial, such as a glass vial. In otherembodiments, the single-use container is a syringe, such as apolypropylene syringe.

In some embodiments, the present disclosure provides a single-usecontainer comprising about 10 mL of a composition comprising about 38 mgof ephedrine (e.g., (−)-ephedrine), about 90 mg of sodium chloride, andwater (e.g., water for injection). In some embodiments, the single-usecontainer is a glass vial. In some embodiments, the single-use containeris a syringe.

In some embodiments, the present disclosure provides a single-usecontainer comprising about 10 mL of a composition comprising about 50 mgof ephedrine sulfate (e.g., (−)-ephedrine sulfate), about 90 mg ofsodium chloride, and water (e.g., water for injection). In someembodiments, the single-use container is a glass vial. In someembodiments, the single-use container is a syringe.

In some embodiments, the present disclosure provides a single-usecontainer comprising about 10 mL of a composition comprising about 46 mgof ephedrine hydrochloride (e.g., (−)-ephedrine hydrochloride), about 90mg of sodium chloride, and water (e.g., water for injection). In someembodiments, the single-use container is a glass vial. In someembodiments, the single-use container is a syringe.

In some embodiments, the present disclosure provides a shelf-stablecomposition comprising ephedrine or an ephedrine salt (e.g., ephedrinesulfate) that does not include a preservative, such as benzyl alcohol.In some embodiments, the shelf-stable composition comprises ephedrine oran ephedrine salt (e.g., ephedrine sulfate), an isotonic agent (e.g.,sodium chloride) and water, but does not include a preservative (e.g.,benzyl alcohol). In some embodiments, the shelf-stable compositioncomprises ephedrine sulfate (e.g., (−)-ephedrine sulfate), sodiumchloride and water, but does not include benzyl alcohol.

In some embodiments, the prese disclosure provides a shelf-stablecomposition comprising ephedrine or an ephedrine salt (e.g., ephedrinesulfate) that does not include a chelating agent, such as EDTA. In someembodiments, the shelf-stable composition comprises ephedrine or anephedrine salt (e.g., ephedrine sulfate), an isotonic agent (e.g.,sodium chloride) and water, but does not include a chelating agent(e.g., EDTA). In some embodiments, the shelf-stable compositioncomprises ephedrine sulfate (e.g., (−)-ephedrine sulfate), sodiumchloride and water, but does not include EDTA.

In some embodiments, the present disclosure provides a shelf-stablecomposition comprising ephedrine or an ephedrine salt (e.g., ephedrinesulfate) that does not include a preservative (e.g., benzyl alcohol) ora chelating agent (e.g., EDTA). In some embodiments, the shelf-stablecomposition comprises ephedrine or an ephedrine salt (e.g., ephedrinesulfate), an isotonic agent (e.g., sodium chloride) and water, but doesnot include a preservative (e.g., benzyl alcohol) or a chelating agent(e.g., EDTA). In some embodiments, the shelf-stable compositioncomprises ephedrine sulfate (e.g., (−)-ephedrine sulfate), sodiumchloride and water, but does not include benzyl alcohol or EDTA.

In some embodiments, a composition of the present disclosure has a pHvalue of 4.5 to 7.0. In some embodiments, the composition has a pH valueof 5.5 to 6.5. In some embodiments, the composition has a pH value ofabout 5.6 to 6.2. In some embodiments, the composition has a pH value ofabout 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7,about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or about7.0.

In some embodiments, a composition of the present disclosure includes nomore than 10 colony forming units (“CFU”) per mL, for example no morethan 10 CFU/mL, no more than 9 CFU/mL, no more than 8 CFU/mL, no morethan 7 CFU/mL, no more than 6 CFU/mL, no more than 5 CFU/mL, no morethan 4 CFU/mL, no more than 3 CFU/mL, no more than 2 CFU/mL, no morethan 1 CFU/mL, no more than 0.5 CFU/mL, no more than 0.4 CFU/mL, no morethan 0.3 CFU/mL, no more than 0.2 CFU/mL, or no more than 0.1 CFU/mL.

In some embodiments, a composition of the present disclosure includesbacterial endotoxins in an amount of no more than 1.7 Eu/mg, no morethan 1.6 Eu/mg, no more than 1.5 Eu/mg, no more than 1.4 Eu/mg, no morethan 1.3 Eu/mg, no more than 1.2 Eu/mg, no more than 1.1 Eu/mg, no morethan 1.0 Eu/mg, no more than 0.9 Eu/mg, no more than 0.8 Eu/mg, no morethan 0.7 Eu/mg, no more than 0.6 Eu/mg, no more than 0.5 Eu/mg, no morethan 0.4 Eu/mg, no more than 0.3 Eu/mg, no more than 0.2 Eu/mg, or nomore than 0.1 Eu/mg.

In some embodiments, the present disclosure provides a compositioncomprising ephedrine sulfate in water, wherein the ephedrine sulfate ispresent at a concentration of about 1 mg/mL to about 10 mg/mL. In someembodiments, the ephedrine sulfate is present at a concentration ofabout 2 mg/mL to about 8 mg/mL. In some embodiments, the ephedrinesulfate is present at a concentration of about 3 mg/mL to about 7 mg/mL.In some embodiments, the ephedrine sulfate is present at a concentrationof about 4 mg/mL to about 6 mg/mL. In some embodiments, the ephedrinesulfate is present at a concentration of about 5 mg/mL. In someembodiments, the composition further comprises sodium chloride. In someembodiments, the sodium chloride is present in an amount of about 9mg/mL. In some embodiments, the composition is stable when stored at 20°C. for at least 12 months. In some embodiments, the composition does notinclude dextrose. In some embodiments, the composition does not includea preservative such as benzyl alcohol. In some embodiments, thecomposition does not include a chelating agent such as EDTA. In someembodiments, the composition consists essentially of ephedrine sulfate,sodium chloride and water. In some embodiments, the composition consistsof ephedrine sulfate, sodium chloride and water. In some embodiments,the ephedrine sulfate is (−)-ephedrine sulfate.

In some embodiments, the present disclosure provides a sterileprediluted medicament comprising about 3.8 mg/mL of ephedrine or anequimolar amount of an ephedrine salt; about 9 mg/mL sodium chloride;and water. In some embodiments, the medicament does not includedextrose. In some embodiments, the medicament does not include benzylalcohol. In some embodiments, a total volume of the medicament is about10 mL. In some embodiments, the medicament is housed in a vial. In someembodiments, after storage at about 20° C., the medicament comprises atleast 3 mg/mL of the ephedrine or a molar equivalent of the ephedrinesalt. In some embodiments, the ephedrine or ephedrine salt is ephedrinesulfate. In some embodiments, the ephedrine sulfate is (−)-ephedrinesulfate.

In some embodiments, the present disclosure provides a ready-to-use unitdose form comprising about 3.8 mg/mL of ephedrine or an equimolar amountof an ephedrine salt (e.g., about 5 mg/mL of ephedrine sulfate); about 9mg/mL of sodium chloride; and water. In some embodiments, theready-to-use unit dose form is housed in a vial. In some embodiments,the ready-to-use unit dose form has a total volume of about 10 mL. Insome embodiments, the ready-to-use unit dose form does not includedextrose. In some embodiments, the ready-to-use unit dose form does notinclude benzyl alcohol. In some embodiments, after storage at about 20°C., the ready-to-use unit dose form comprises at least 3 mg/mL of theephedrine or an equimolar amount of the ephedrine salt (e.g., at least 4mg/mL of ephedrine sulfate).

In some embodiments, the present disclosure provides a packagedpharmaceutical product comprising a vial; and a solution housed withinthe vial, wherein the solution comprises, consists essentially of, orconsists of about 5 mg/mL of ephedrine sulfate; about 9 mg/mL sodiumchloride; and water. In some embodiments, the solution has a totalvolume of about 10 mL. In some embodiments, the solution does notinclude dextrose. In some embodiments, the vial comprises, consistsessentially of, or consists of glass. In some embodiments, the vialcomprises, consists essentially of, or consists of polypropylene. Insome embodiments, the solution is stable when stored at about 20° C. forat least 12 months. In some embodiments, after storage at about 20° C.for at least 12 months, the solution comprises ephedrine sulfate at aconcentration of about 4 mg/mL to about 6 mg/mL. In some embodiments,after storage at about 20° C. for at least 12 months, the solutioncomprises at least 4 mg/mL of ephedrine sulfate. In some embodiments,after storage at about 20° C. for at least 12 months, the solutioncomprises at least 4.5 mg/mL ephedrine sulfate. In some embodiments, theephedrine sulfate is (−)-ephedrine sulfate.

Methods of Using Ready-to-Use Ephedrine Compositions

The present disclosure provides methods of using ready-to-usecompositions comprising ephedrine or an ephedrine salt. Generally, themethods disclosed herein do not require a clinician to dilute theready-to-use composition before administering the ready-to-usecomposition to a subject. In some embodiments, the risk of microbialcontamination to the subject is lower, such as substantially lower, whenadministered ready-to-use ephedrine compositions consistent with thepresent disclosure compared to the risk of microbial contamination tosubjects (e.g., similarly situated subjects) who are administeredephedrine compositions that require dilution of a concentrated packagedephedrine pharmaceutical composition.

In some embodiments, the present disclosure provides a method ofreducing a risk of microbial infection associated with administration ofephedrine or an ephedrine salt (e.g., ephedrine sulfate) to a subject inneed thereof.

In some embodiments, a risk of microbial contamination to a subjectadministered a ready-to-use composition comprising ephedrine or anephedrine salt (e.g., ephedrine sulfate) consistent with the presentdisclosure is lower, or substantially lower, than a risk of microbialcontamination to a second subject administered ephedrine sulfate diluted(e.g., diluted by a clinician) to a concentration of 5 mg/mL. In somesuch embodiments, the second subject receives ephedrine sulfate preparedby mixing (e.g., diluting) a concentrated ephedrine sulfate compositionfrom a sterilized packaged pharmaceutical product comprising 50 mg/mLephedrine sulfate with a diluent, such as saline, to form the dilutedephedrine sulfate composition.

In some embodiments, the present disclosure provides a method ofadministering ephedrine sulfate to a subject in need thereof, the methodcomprising drawing a composition comprising ephedrine sulfate from asterile premixed pharmaceutical product into a syringe; and injectingthe composition into the subject using the syringe, wherein theephedrine sulfate is present in the composition in an amount of about 5mg/mL. In some embodiments, the composition further comprises sodiumchloride in an amount of about 9 mg/mL. In some embodiments, thecomposition further comprises water. In some embodiments, thecomposition does not include dextrose. In some embodiments, the methoddoes not include diluting the sterile premixed pharmaceutical productbefore the step of injecting the composition into the subject using thesyringe. In some embodiments, the composition housed within the vial ofthe sterile premixed pharmaceutical product is stable when stored atabout 20° C. for at least 12 months. In some embodiments, after storageat about 20° C. for at least 12 months, the composition comprisesephedrine sulfate in an amount of about 4 mg/mL to about 6 mg/mL. Insome embodiments, the ephedrine sulfate is (−)-ephedrine sulfate.

In some embodiments, the present disclosure provides a method oftreating hypotension in a subject in need thereof, the method comprisingdrawing an effective amount of a packaged composition comprisingephedrine or an ephedrine salt into a syringe; and injecting theeffective amount of the packaged composition into the subject in needthereof. In some embodiments, the packaged composition comprisesephedrine or an ephedrine salt in an amount equivalent to about 3.8mg/mL ephedrine. In some embodiments, the packaged composition furthercomprises sodium chloride in an amount of about 9 mg/mL. In someembodiments, the packaged composition further comprises water. In someembodiments, the packaged composition does not include dextrose. In someembodiments, the method does not include diluting the packagedcomposition before the step of injecting the effective amount of thepackaged composition into the subject in need thereof. In someembodiments, the packaged composition is stable when stored at about 20°C. for at least 12 months. In some embodiments, after storage at about20° C. for at least 12 months, the packaged composition comprisesephedrine sulfate in an amount of about 4 mg/mL to about 6 mg/mL. Insome embodiments, the ephedrine or ephedrine salt is (−)-ephedrinesulfate. In some embodiments, the method further comprises determining alow blood pressure reading in the subject before the step of drawing theeffective amount of the packaged composition comprising ephedrine or anephedrine salt into the syringe. In some embodiments, the hypotension isclinically important hypotension. In some embodiments, the clinicallyimportant hypotension is clinically important hypotension in the settingof anesthesia. In some embodiments, the method further comprisesdetecting a hypotensive state (e.g., a clinically important hypotensivestate) associated with the subject before injecting the effective amountof the packaged composition into the subject.

In some embodiments, the present disclosure provides a method ofincreasing a blood pressure in a subject in need thereof, the methodcomprising determining a low blood pressure reading associated with asubject; drawing about 1 mL to about 10 mL of a packaged compositioncomprising about 5.0 mg/mL ephedrine sulfate into a syringe; injectingabout 1 mL to about 10 mL of the packaged composition into the subjectin need thereof, wherein the blood pressure reading associated with thesubject increases after the step of injecting the packaged compositioninto the subject in need thereof, and wherein the method does notinclude diluting the packaged composition before the step of injectingthe packaged composition into the subject in need thereof. In someembodiments, the packaged composition further comprises sodium chloridein an amount of about 9 mg/mL. In some embodiments, the packagedcomposition further comprises water. In some embodiments, the packagedcomposition does not include dextrose. In some embodiments, the methodfurther comprises determining a second blood pressure reading associatedwith the subject after the step of injecting the packaged compositioninto the subject, wherein the second blood pressure reading ishypotensive. In some embodiments, the method further comprises injectingabout 1 mL to about 10 mL of the packaged composition into the subjectafter the step of determining the second hypotensive blood pressurereading associated with the subject. In some embodiments, the packagedcomposition is stable when stored at about 20° C. for at least 12months. In some embodiments, after storage at about 20° C. for at least12 months, the packaged composition comprises ephedrine sulfate in anamount of at least about 4 mg/mL. In some embodiments, after storage atabout 20° C. for at least 12 months, the packaged composition comprisesephedrine sulfate in an amount of at least about 4.5 mg/mL. In someembodiments, the ephedrine sulfate is (−)-ephedrine sulfate.

Methods of Making Ready-to-Use Ephedrine Compositions

The present disclosure further provides methods of making ready-to-usecompositions comprising ephedrine or an ephedrine salt.

In general terms, ephedrine or an ephedrine salt (e.g., ephedrinesulfate) is combined with sodium chloride or dextrose in water forinjection and mixed to form a clear, colorless solution. In someembodiments, the pH of the solution is adjusted to 4.5 to 7.0 using anacid (e.g., glacial acetic acid) or a base (e.g., sodium hydroxide). Thefinal concentration of ephedrine or the ephedrine salt in the optionallypH-adjusted solution is equivalent to about 3.8 mg/mL of ephedrine freebase. Accordingly, in embodiments wherein the ephedrine or the ephedrinesalt is ephedrine sulfate, the final concentration of ephedrine sulfatein the optionally pH-adjusted solution is about 5.0 mg/mL. Inembodiments wherein the ephedrine or the ephedrine salt is ephedrinehydrochloride, the final concentration of ephedrine hydrochloride in theoptionally pH-adjusted solution is about 4.6 mg/mL. The concentration ofsodium chloride or dextrose in the optionally pH-adjusted solutionshould be isotonic to human serum (e.g., about 9 mg/mL sodium chlorideor about 5% dextrose).

The ephedrine or ephedrine salt solution must be sterilized before useby a clinician. In some embodiments, the ephedrine or ephedrine saltsolution is placed in vials (e.g., glass or plastic single-use vials)and then sterilized by any suitable method known in the art.

In some embodiments, the present disclosure provides a method of makinga ready-to-use pharmaceutical composition comprising ephedrine or anephedrine salt, the method comprising combining ephedrine or anephedrine salt, sodium chloride and water to provide a solutioncomprising about 3.8 mg/mL ephedrine or an equimolar amount of anephedrine salt, and about 9 mg/mL sodium chloride; and thereaftersterilizing the solution to provide a ready-to-use pharmaceuticalcomposition comprising ephedrine or an ephedrine salt. In someembodiments, the method further comprises placing the solution in one ormore vials before the step of sterilizing. In some embodiments, thesolution does not include dextrose. In some embodiments, thepharmaceutical composition is stable when stored at about 20° C. for atleast 12 months. In some embodiments, after storage at about 20° C. forat least 12 months, the pharmaceutical composition comprises an amountof the ephedrine or the ephedrine salt that is at least 80% of the about3.8 mg/mL ephedrine or the equimolar amount of the ephedrine salt. Insome embodiments, the ephedrine or the ephedrine salt is ephedrinesulfate. In some embodiments, the ephedrine salt is (−)-ephedrinesulfate. In some embodiments, the equimolar amount of the ephedrine saltis about 5 mg/mL of the ephedrine sulfate. In some embodiments, theephedrine or the ephedrine salt is ephedrine hydrochloride. In someembodiments, the ephedrine hydrochloride is (−)-ephedrine hydrochloride.In some embodiments, the equimolar amount of the ephedrine salt is about4.6 mg/mL of the ephedrine hydrochloride.

EXAMPLES

Aspects of embodiments may be further understood in light of thefollowing examples, which should not be construed as limiting in anyway.

Example 1. Ready-to-Use Ephedrine Sulfate Composition

A ready-to-use injectable composition of ephedrine sulfate was preparedat 50 L scale by combining ephedrine sulfate USP/EP powder (Lot#18130597, Siegfried PharmaChemikalien, Minden Germany), sodium chlorideUSP/EP (Lot #18804697, Merck & Co., Kenilworth, N.J.), and water forinjection in the amounts shown in Table 1, below, in a 200 L stainlesssteel vessel.

TABLE 1 Compendial Amount per Component Designation 10 cc vial Ephedrinesulfate USP/EP 50 mg Sodium chloride USP/EP 90 mg Water for injectionUSP/EP q.s. to 10 mL

Two 20 mL vials of the mixed solution were sampled at this stage, andindicated that ephedrine sulfate was present in the solution at100.2%-102.2% of the desired 5 mg/mL amount. A bioburden test of 200 mLof the mixed solution at this stage also revealed an acceptable level ofbiological components (0-0.1 CFU/mL).

After mixing, the solution was filtered through Opticap XL 4 capsuledurapore membranes (lot #18131597, Merck Millipore, Burlington, Mass.)before filling 10 cc clear glass type I vials (Lot #18500797,Gerresheimer/Bormioli, Dusseldorf, Germany) that had been washed anddepyrogenized. The vials were capped with chlorobutyl fluorotic coatedstoppers (lot #18803297, West Pharma, Exton, Pa.), and flip-off caps(lot #18700897, Capsulit S.p.A., Roncello, Italy).

The pH level of the solution in the vials ranged from 5.6-6.2, wellwithin the acceptable range of 4.5-7.0. Ephedrine sulfate was present inthe solution in the vials in amounts ranging from 100.8% to 102.5% ofthe desired 5 mg/mL concentration. Bioburden testing of the solution inthe vials revealed 0 CFU/mL.

The capped vials were crimped and sterilized by the overkill approach at122.1° C. for 15 minutes in steel cassettes in an A601A autoclave.

Visual inspection of the terminally sterilized vials revealed noextraneous matter, low product volume or cosmetic defects. Thesterilized vials passed sterility testing consistent with USP method<71> and passed bacterial endotoxins testing by USP method <87> (≤1.7Eu/mg).

Bioburden testing on twenty pooled stoppers after filling indicated arange of 0-0.5 CFU/mL.

Analysis of three lots of ready-to-use 10-mL vials of ephedrine sulfateprepared by this method is shown Table 2, below:

TABLE 2 Analysis Lot 1 Lot 2 Lot 3 Appearance Clear, colorless, novisible particulate matter Identification by UV UV spectrum conforms toUSP Reference Standard Identification by Retention time of ephedrinepeak corresponds to HPLC USP Reference Standard Volume in Container 10.6 mL  10.7 mL  10.6 mL Osmolality   316 mOsm/kg   314 mOsm/kg   319mOsm/kg pH  5.8  5.5  5.8 (−)-Ephedrine 101.1% of label claim 101.0% oflabel claim 101.4% of label claim (+)-Ephedrine ND* ND ND IndividualUnknown <LOQ** <LOQ <LOQ Impurities Total Impurities <LOQ <LOQ <LOQParticulate Matter ≥10 μm: 9 per ≥10 μm: 19 per ≥10 μm: 41 percontainer; container; container; ≥25 μm: 2 per ≥25 μm: 5 per ≥25 μm: 11per container container container Sterility (USP <71>) Pass Pass PassBacterial Endotoxins Pass Pass Pass (USP <87>) *ND = None Detected.**LOQ = Level of Quantification.

Example 2. Real-Time Stability of Ready-to-Use Ephedrine SulfateCompositions

10-mL batches of ephedrine sulfate injection, 5 mg/mL, were prepared ineach of 510 10-mL Type I flint glass vials (Gerresheimer/Bormioli),closed with 20 mm chlorobutyl flurotec-coated stoppers (West) and sealedwith a 20 mm flip-off aluminum crimp seal (Capsult) in a productionfacility using standard production equipment, processes, personnel andprocedures, all consistent with the method disclosed in Example 1.Ephedrine sulfate API was sourced from Siegfried PharmaChemikalienMinden GmbH (Germany).

The vials were stored at 25+/−2° C. and 60+/−5% relative humidity (RH)for 24 months in a controlled access, secure cabinet or security chamberand only withdrawn for testing. Some vials were stored upright, whileothers were stored inverted (e.g., liquid in contact with the vialclosures). Samples were identified and records were kept in a stabilitystudy log.

Vials were tested according to the parameters shown in Table 3, at thetime points shown in Table 4, and by upright/inverted vial designationas shown in Table 5, below:

TABLE 3 Test Specification Test Method Vial Counts Visual Inspection: A)10 cc flint glass QC-021 Use assay vials A) Physical vial sealed with aappearance stopper and B) Clarity aluminum seal C) Particulate B) Clearmatter C) No visible D) Visual color particulates D) Colorless pH 4.5 to7.0 USP <791>  2 Particulate matter For particles ≥10 μm: USP <788> 10(HIAC) NMT 6000 per container; For particles ≥25 μm: NMT 600 percontainer Osmolality  270-330 mOsm/kg QC-028  2 Ephedrine sulfate95.0-105.0% of label EPH-001  3 assay (5 mg/mL) claim Enantiomericpurity NMT 0.5% (+)- EPH-003  2 (Chiral HPLC) 1S, 2R-Ephedrine Relatedsubstances ≤0.2% Unknown EPH-001 Use assay vials individual impurity;≤0.75% Total impurities Sterility Sterile USP <71> 20 Bacterialendotoxins NMT 7.0 EU/mg USP <85>  3

TABLE 4 Data point Timing Time Zero Date on which samples were placedinto the stability chamber  3 Months Pull date for analysis occurs +/−1week of the 3-month anniversary date of Time Zero  6 Months Pull datefor analysis occurs +/−1 week of the 6-month anniversary date of TimeZero  9 Months Pull date for analysis occurs +/−1 week of the 9-monthanniversary date of Time Zero 12 Months Pull date for analysis occurs+/−2 weeks of the 12-month anniversary date of Time Zero 18 Months Pulldate for analysis occurs +/−2 weeks of the 18-month anniversary date ofTime Zero 24 Months Pull date for analysis occurs +/−4 weeks of the24-month anniversary date of Time Zero

TABLE 5 Time Point (months) Test 0 3 6 9 12 18 24 Visual Inspection: UUI UI UI UI UI UI A) Physical appearance B) Clarity C) Particulatematter D) Visual color pH U UI UI UI UI UI UI Particulate matter U UI UIUI UI UI UI (HIAC) Osmolality U NP NP NP UI NP UI Ephedrine sulfate U UIUI UI UI UI UI assay (5 mg/mL) Enantiomeric purity U UI UI UI UI UI UI(Chiral HPLC) Related substances U UI UI UI UI UI UI Sterility U NP NPNP I NP NP Bacterial U NP NP NP NP NP I endotoxins Elemental NP NP NP NPI NP I Impurities Container/Closure UI NP NP NP NP NP I IntegrityTesting (CCIT) U: Upright orientation; I: Inverted orientation; NP: Notperformed

The number of vials pulled for testing at each time point is summarizedin Table 6 below:

TABLE 6 Time Point (months) Test 0 3 6 9 12 18 24 Upright 46 17 17 17 1917 19 Inverted NP 17 17 17 39 17 42 NP: Not performed

Quantitative analyses were plotted as mean values as a function of time,while qualitative analyses were recorded and summarized so that profilechanges could be reviewed and conclusions drawn.

Results of Real-Time Stability Study

-   -   1. Physical Appearance

Specification:

-   -   A) 10 cc flint glass vial seal with a stopper and aluminum seal    -   B) Clear    -   C) No visible particulates    -   D) Colorless

TABLE 7 Physical Appearance Results Stability Time Point 3 6 9 12 18 24months months months months months months Lot Initial Up Inv Up Inv UpInv Up Inv Up Inv Up Inv 1 MR MR MR MR MR MR MR MR MR MR MR MR MR 2 MRMR MR MR MR MR MR MR MR MR MR MR MR 3 MR MR MR MR MR MR MR MR MR MR MRMR MR MR = Meets Requirements

-   -   2. Osmolality

Specification: 270-330 mOsm/kg

TABLE 8 Osmolality Results Stability Time Point 3 6 9 12 18 24 monthsmonths months months months months Lot Initial Up Inv Up Inv Up Inv UpInv Up Inv Up Inv 1 316 NP NP NP NP NP NP 320 319 NP NP 327 323 2 314 NPNP NP NP NP NP 317 316 NP NP 318 317 3 319 NP NP NP NP NP NP 318 317 NPNP 319 318 NP = Not Performed

-   -   3. pH

Specification: Between 4.5 and 7.0

TABLE 9 pH Results Stability Time Point 3 6 9 12 18 24 months monthsmonths months months months Lot Initial Up Inv Up Inv Up Inv Up Inv UpInv Up Inv 1 5.8 6.1 5.9 5.4 5.5 5.9 5.8 6.7 6.2 5.7 5.7 5.7 5.6 2 5.55.8 5.8 5.7 5.6 5.7 5.7 6.5 6.6 5.8 5.7 5.6 5.6 3 5.8 5.9 6.2 6.0 5.95.8 5.9 6.5 6.6 5.8 5.8 5.7 5.7

-   -   4. Ephedrine Sulfate Assay (5 mg/mL)

Specification: 95.0%-105.0% of label claim

TABLE 10 Ephedrine Sulfate Assay Results Stability Time Point 3 months 6months 9 months 12 months 18 months 24 months Lot Initial Up Inv Up InvUp Inv Up Inv Up Inv Up Inv 1 101.1% 101.0 100.9 100.9 101.1 101.5 101.3100.7 100.7 101.0 101.2 102.2 101.6 2 101.0% 100.4 100.4 100.3 100.8100.8 102.0 100.1 100.0 100.8 101.1 101.5 101.0 3 101.4% 100.7 100.4100.6 100.9 101.8 101.0  99.4  99.2 101.0 100.5 101.1 101.2

-   -   5. Enantiomeric Purity

Specification: (+)-1S,2R-Ephedrine, NMT 0.5% by chiral HPLC

TABLE 11 Enantiomeric Purity Results Stability Time Point 3 months 6months 9 months 12 months 18 months 24 months Lot Initial Up Inv Up InvUp Inv Up Inv Up Inv Up Inv 1 ND <LOQ <LOQ ND ND ND ND ND ND ND ND ND ND2 ND <LOQ <LOQ ND ND ND ND ND ND ND ND ND ND 3 ND <LOQ <LOQ ND ND ND NDND ND ND ND ND ND ND = None Detected; LOQ = Limit of Quantitation

-   -   6. Related Substance: Any unknown individual impurity

Specification: Any unknown individual impurity, ≤0.2% by HPLC

TABLE 12A Related Substances Results: Any unknown individual impurityStability Time Point 3 months 6 months 9 months 12 months 18 months 24months Lot Initial Up Inv Up Inv Up Inv Up Inv Up Inv Up Inv 1 <LOQ <LOD<LOQ ND <LOQ 0.0 0.0 <LOQ <LOQ <LOQ <LOQ <LOQ 0.2% 2 <LOQ <LOQ <LOD <LOQ<LOQ 0.0 0.0 <LOQ <LOQ <LOQ <LOQ 0.1% 0.1% 3 <LOQ <LOQ <LOQ <LOQ ND 0.00.0 <LOQ <LOQ <LOQ <LOQ 0.1% <LOQ LOQ = Limit of Quantitation; LOD =Limit of Detection; ND = None Detected

-   -   7. Related Substance: Total impurities

Specification:

-   -   Total impurities, ≤0.75% by HPLC

TABLE 12B Related Substances Results: Total impurities Stability TimePoint 3 months 6 months 9 months 12 months 18 months 24 months LotInitial Up Inv Up Inv Up Inv Up Inv Up Inv Up Inv 1 <LOQ <LOD <LOQ ND<LOQ 0.02 0.02 <LOQ <LOQ <LOQ <LOQ <LOQ 0.19% 2 <LOQ <LOQ <LOD <LOQ <LOQ0.02 0.02 <LOQ <LOQ <LOQ <LOQ 0.09% 0.09% 3 <LOQ <LOQ <LOQ <LOQ ND 0.020.01 <LOQ <LOQ <LOQ <LOQ 0.11% <LOQ LOQ = Limit of Quantitation; LOD =Limit of Detection; ND = None Detected

-   -   8. Particulate Matter

Specification:

-   -   A) For particles ≥10 μm, NMT 6000 per container by HIAC    -   B) For particles ≥25 μm, NMT 600 per container by HIAC

TABLE 13 Particulate Matter Results Stability Time Point 3 months 6months 9 months 12 months 18 months 24 months Lot Initial Up Inv Up InvUp Inv Up Inv Up Inv Up Inv 1 A) 9  A) 94  A) 167 A) 1113 A) 363 A) 133A) 94  A) 149 A) 199 A) 73  A) 59  A) 174 A) 139 B) 2  B) 0  B) 0  B)1   B) 0  B) 1  B) 0  B) 1  B) 0  B) 0  B) 0  B) 1  B) 0  2 A) 19 A) 96 A) 63  A) 717  A) 273 A) 215 A) 189 A) 83  A) 134 A) 45  A) 124 A) 254A) 518 B) 5  B) 0  B) 0  B) 1   B) 0  B) 0  B) 1  B) 0  B) 1  B) 0  B)1  B) 0  B) 0  3 A) 41 A) 315 A) 45  A) 673  A) 354 A) 209 A) 237 A) 173A) 97  A) 201 A) 85  A) 145 A) 121 B) 11 B) 0  B) 0  B) 4   B) 1  B) 0 B) 0  B) 0  B) 0  B) 0  B) 1  B) 0  B) 1 

-   -   9. Sterility

Specification: Sterile

TABLE 14 Sterility Results Stability Time Point 3 months 6 months 9months 12 months 18 months 24 months Lot Initial Up Inv Up Inv Up Inv UpInv Up Inv Up Inv 1 Sterile NP NP NP NP NP NP NP Sterile NP NP NP NP 2Sterile NP NP NP NP NP NP NP Sterile NP NP NP NP 3 Sterile NP NP NP NPNP NP NP Sterile NP NP NP NP NP = Not Performed

-   -   10. Bacterial Endotoxins

Specification: NMT 7.0 EU/mg

TABLE 15 Bacterial Endotoxins Results Stability Time Point 3 months 6months 9 months 12 months 18 months 24 months Lot Initial Up Inv Up InvUp Inv Up Inv Up Inv Up Inv 1 MR NP NP NP NP NP NP NP NP NP NP NP <0.2 2MR NP NP NP NP NP NP NP NP NP NP NP <0.2 3 MR NP NP NP NP NP NP NP NP NPNP NP <0.2 MR = Meets Requirements; NP = Not Performed

-   -   11. Elemental Impurities

Specification: Meets the requirements of USP <232>

TABLE 16 Elemental Impurities Results Stability Time Point 3 months 6months 9 months 12 months 18 months 24 months Lot Initial Up Inv Up InvUp Inv Up Inv Up Inv Up Inv 1 NP NP NP NP NP NP NP NP MR NP NP NP MR 2NP NP NP NP NP NP NP NP MR NP NP NP MR 3 NP NP NP NP NP NP NP NP MR NPNP NP MR MR = Meets Requirements; NP = Not Performed

-   -   12. Container/Closure Integrity Testing (CCIT)

Specification: Integral

TABLE 17 CCIT Results Stability Time Point 3 months 6 months 9 months 12months 18 months 24 months Lot Initial Up Inv Up Inv Up Inv Up Inv UpInv Up Inv 1 MR NP NP NP NP NP NP NP NP NP NP NP MR 2 MR NP NP NP NP NPNP NP NP NP NP NP MR 3 MR NP NP NP NP NP NP NP NP NP NP NP MR MR = MeetsRequirements; NP = Not Performed

Example 3. Accelerated Stability Study of Ready-to-Use Ephedrine SulfateCompositions

10-mL batches of ephedrine sulfate injection, 5 mg/mL, were prepared ineach of 510 10-mL Type I flint glass vials (Gerresheimer/Bormioli),closed with 20 mm chlorobutyl flurotec-coated stoppers (West) and sealedwith a 20 mm flip-off aluminum crimp seal (Capsult) in a productionfacility using standard production equipment, processes, personnel andprocedures, all consistent with the method disclosed in Example 1.Ephedrine sulfate API was sourced from Siegfried PharmaChemikalienMinden GmbH (Germany).

The vials were stored at 40+/−2° C. and 75+/−5% relative humidity (RH)for 6 months in a controlled access, secure stability chamber and onlywithdrawn for testing. Some vials were stored upright, while others werestored inverted (e.g., liquid in contact with the vial closures).Samples were identified and records were kept in a stability study log.

Vials were tested according to the parameters shown in Table 18, at thetime points shown in Table 19, and by upright/inverted vial designationas shown in Table 20, below:

TABLE 18 Test Specification Test Method Vial Counts Visual Inspection:A) 10 cc flint glass QC-021 Use assay vials A) Physical vial sealed witha appearance stopper and B) Clarity aluminum seal C) Particulate B)Clear matter C) No visible D) Visual color particulates D) Colorless pH4.5 to 7.0 USP <791>  2 Particulate matter For particles ≥10 μm: USP<788> 10 (HIAC) NMT 6000 per container; For particles ≥25 μm: NMT 600per container Osmolality  270-330 mOsm/kg QC-028  2 Ephedrine sulfate95.0-105.0% of label EPH-001  3 assay (5 mg/mL) claim Enantiomericpurity NMT 1.0% (+)- EPH-003  2 (Chiral HPLC) 1S, 2R-Ephedrine Relatedsubstances ≤0.2% Unknown EPH-001 Use assay vials individual impurity;≤0.75% Total impurities Sterility Sterile USP <71> 20 Bacterialendotoxins NMT 7.0 EU/mg USP <85>  3

TABLE 19 Data point Timing Time Zero Date on which samples were placedinto the stability chamber 1 Month Pull date for analysis occurs +/−1week of the 1-month anniversary date of Time Zero 3 Months Pull date foranalysis occurs +/−1 week of the 3-month anniversary date of Time Zero 6Months Pull date for analysis occurs +/−1 week of the 6-monthanniversary date of Time Zero

TABLE 20 Time Point (months) Test 0 1 3 6 Visual Inspection: UI UI UI UIA) Physical appearance B) Clarity C) Particulate matter D) Visual colorpH UI UI UI UI Particulate matter UI UI UI UI (HIAC) Osmolality NP NP NPUI Ephedrine sulfate UI UI UI UI assay (5 mg/mL) Enantiomeric purity UUI UI UI (Chiral HPLC) Related substances U UI UI UI U: Uprightorientation; I: Inverted orientation; NP: Not performed

The number of vials pulled for testing at each time point is summarizedin Table 21 below:

TABLE 21 Time Point (months) Test 0 1 3 6 Upright NP 17 17 19 InvertedNP 17 17 19 NP: Not performed

Quantitative analyses were plotted as mean values as a function of time,while qualitative analyses were recorded and summarized so that profilechanges can be reviewed and conclusions drawn.

Results of Accelerated Stability Study

-   -   1. Physical Appearance

Specification:

-   -   A) 10 cc flint glass vial seal with a stopper and aluminum seal    -   B) Clear    -   C) No visible particulates    -   D) Colorless

TABLE 22 Physical Appearance Results Stability Time Point 1 3 6 monthmonths months Lot Up Inv Up Inv Up Inv 1 MR MR MR MR MR MR 2 MR MR MR MRMR MR 3 MR MR MR MR MR MR MR = Meets Requirements

-   -   2. Osmolality

Specification: 270-330 mOsm/kg

TABLE 23 Osmolality Results Stability Time Point 1 month 3 months 6months Lot Up Inv Up Inv Up Inv 1 NP NP NP NP 318 320 2 NP NP NP NP 315314 3 NP NP NP NP 318 314 NP = Not Performed

-   -   3. pH

Specification: Between 4.5 and 7.0

TABLE 24 pH Results Stability Time Point 1 month 3 months 6 months LotUp Inv Up Inv Up Inv 1 5.6 5.7 5.8 5.6 6.0 6.1 2 5.7 5.7 5.8 5.8 6.2 5.83 5.9 5.8 5.9 5.8 5.8 5.9

-   -   4. Ephedrine Sulfate Assay (5 mg/mL)

Specification: 95.0%-105.0% of label claim

TABLE 25 Ephedrine Sulfate Assay Results Stability Time Point 1 month 3months 6 months Lot Up Inv Up Inv Up Inv 1 101.5% 101.6% 101.3% 100.9%100.8% 100.9% 2 100.8% 100.3% 100.7% 100.3% 100.7% 99.9% 3 100.8% 100.7%100.4% 100.6% 100.6% 100.1%

-   -   5. Enantiomeric Purity

Specification: (+)-1S,2R-Ephedrine, NMT 0.5% by chiral HPLC

TABLE 26 Enantiomeric Purity Results Stability Time Point 1 month 3months 6 months Lot Up Inv Up Inv Up Inv 1 ND ND <LOQ <LOQ ND ND 2 ND ND<LOQ <LOQ ND ND 3 ND ND <LOD <LOQ ND ND ND = None Detected; LOQ = Limitof Quantitation

-   -   6. Related Substance

Specification:

-   -   A) Unknown individual impurities, 0.2%    -   B) Total impurities, 0.75%

TABLE 27 Related Substances Results Stability Time Point 1 month 3months 6 months Lot Up Inv Up Inv Up Inv 1 A) <LOQ A) <LOQ A) <LOD A)<LOQ A) ND A) <LOQ B) <LOQ B) <LOQ B) <LOD B) <LOQ B) ND B) <LOQ 2 A)<LOQ A) <LOQ A) <LOQ A) <LOQ A) <LOQ A) <LOQ B) <LOQ B) <LOQ B) <LOQ B)<LOQ B) <LOQ B) <LOQ 3 A) <LOQ A) <LOQ A) <LOQ A) <LOD A) <LOQ A) ND B)<LOQ B) <LOQ B) <LOQ B) <LOD B) <LOQ B) ND LOQ = Limit of Quantitation;LOD = Limit of Detection; ND = None Detected

-   -   7. Particulate Matter

Specification:

-   -   A) For particles 10 μm, NMT 6000 per container by HIAC    -   B) For particles 25 μm, NMT 600 per container by HIAC

TABLE 28 Particulate Matter Results Stability Time Point 1 month 3months 6 months Lot Up Inv Up Inv Up Inv 1 A) 455 A) 290 A) 104 A) 128A) 120 A) 363 B) 1  B) 1  B) 0  B) 0  B) 0  B) 0  2 A) 139 A) 389 A) 6 A) 155 A) 271 A) 90  B) 1  B) 1  B) 5  B) 0  B) 1  B) 1  3  A) 1087 A)552 A) 101 A) 101 A) 196 A) 120 B) 5  B) 0  B) 0  B) 1  B) 1  B) 0 

Example 4. Extractable and Leachable Substances Study

Ephedrine Sulfate in 0.9% Sodium Chloride Injection, 50 mg/10 mL, (5mg/mL) was packaged in a 10 cc Type I glass vial with a Flurotec coatedChlorobutyl rubber stopper (20 mm 4110/40, Grey, B2-40 from West). ThisExtractable and Leachable (E&L) study was designed based on theguidelines provided in USP <1663>, <1664>.

Whole stoppers were immersed and refluxed (exposing the uncoated surfaceas well) in extraction solvents offering greater extracting power thanready-to-use ephedrine compositions consistent with the presentdisclosure overnight for a minimum of 12 hours in three solvents: waterpH 3.4, water pH 9.4 and IPA/Water (50/50). Additionally, a leachablesanalysis was performed by QTOF GC-MS, QTOF LC-MS and HPLC for threeexhibit batches of ready-to-use ephedrine sulfate composition samples ofExample 2 that were stored in an inverted orientation for 24 months at25° C.±2° C. and 60%±5% relative humidity (RH). In order to extractmetal impurities, an extractable study was performed on stoppers andvials using 2% HNO₃ and the extracts were screened using ICP-MSanalysis. Additionally, three exhibit batches of ready-to-use ephedrinesulfate composition samples of Example 2 that were stored in an invertedposition for 24 months at 25° C.±2° C. and 60%±5% RH were analyzed forClass 1 and 2A elements.

Summary Results.

The extracts from the extractable study performed on stoppers wereanalyzed by GC-MS for volatile and semi-volatile compounds and by LC-MSfor non-volatile compounds. The control samples were also prepared andanalyzed along with all exposed extractable samples and the drug productstability samples. The MS study was performed by an independentlaboratory using LC-MS and GC-MS to identify and relatively quantify theextractables and leachables in the extracts or in the ready-to-useephedrine sulfate compositions. Subsequently, a leachable study was alsoperformed by a High-Pressure Liquid Chromatography (HPLC) basedvalidated method (EPH-006).

Most of the identified extractables appeared to be originating from theuncoated surface of the stoppers. Extractables included siloxaneoligomers, non-ionic surfactants (Laureth-9 and related), sulfurcompounds, Butylated hydroxytoluene (BHT) and fatty acids (mineralfillers) commonly used in the production of elastomeric components.Another extractable found in the LC-MS analysis was Triethylene glycolwhich is a common plasticizer used in the production of vinyl polymers.During the leachable analysis, a compound consistent withbis(2-ethylhexyl) isophthalate was detected in the ready-to-useephedrine sulfate composition samples at a concentration of 0.15 μg/mLor lower by QTOF-GCMS. Another compound consistent with dichlorobenzoicacid (DCBA) was also detected in the ready-to-use ephedrine sulfatecomposition samples at levels of 1.4 μg/mL or lower by QTOF-LCMS-UV-CAD.Dichlorobenzoic acid was also detected during the HPLC analysis usingtest method EPH-006 at the concentration of 0.7 μg/mL or lower. It is tobe noted that DCBA detected both by the MS study and the HPLC analysiswas also detected previously during the leachable analysis of the18-month samples of the ready-to-use ephedrine sulfate compositions.

Based on MS study and HPLC analysis, the maximum amount ofdichlorobenzoic acid (DCBA found was ˜1.4 ppm (˜0.02% with respect toEphedrine Sulfate) in one sample of ready-to-use ephedrine sulfatecomposition stored in the inverted position for 24 months. As per ICHguidelines (Impurities in New drug products Q3B R2) the identificationthreshold for any impurities that may be present in Ephedrine Sulfate is0.2% and the qualification threshold is 0.5%. The amount of DCBA foundin this inverted stored sample was below the limit of quantitation (LOQ)i.e. <0.1 ppm.

For the evaluation of elemental impurities, the extracts from thestoppers and vials were analyzed by ICP-MS. Results obtained from theICPMS analysis of the extracting solutions indicates that the Class 1,2A and 3 were found to be below the respective established PDEs.

Furthermore, three exhibit batches of ready-to-use ephedrine sulfatecompositions of Example 2 stored in an inverted position for 24 monthsat 25° C.±2° C. and 60%±5% RH were analyzed for Class 1 and 2A elementsby ICP-MS. All tested elemental impurities were found to besignificantly lower their established permitted daily exposure (PDE)values. Therefore, based on the data from this extractable and leachablestudy, the safety risk associated with leachables or metallic impuritiesin the ready-to-use ephedrine sulfate compositions consistent with thepresent disclosure appears to be low.

Extractables Study

Stoppers were extracted using three extraction solvents mentioned below.a) Water adjusted to pH 3.4 using 1N HCl b) Water adjusted to pH 9.4using 1N NaOH c) IPA/Water 50%/50% (v/v) Three sets of 10 stoppers(weight˜16.8 g each) were transferred into three separate 250 mL roundbottom flasks. 100 mL each of pH 3.4 aqueous solution, pH 9.4 aqueoussolution and IPA/Water (50:50 v/v) mixture were transferred into thethree separate above-mentioned round bottom flasks. Each solventcontaining 10 stoppers was refluxed to boiling overnight (minimum 12hours). Reflux was performed for 12 hours each for the IPA/water mixtureand the pH 3.4 solution and 20 hours for the pH 9.4 solution. Resultingsolution from each reflux solvent was analyzed for extractables usingQTOF LC-MS and GC-MS.

The extractable study intended to extract metals was performed on rubberstoppers and glass vials. 10 stoppers were weighed (weight ˜17 g) andtransferred into a 1 L plastic container. Approximately 200 mL(appropriate volume to immerse the stoppers) of 2% HNO₃ solution wastransferred into the container having the stoppers and placed in an ovenmaintained at 60° C. for ˜24 h. Similarly, 5 vials (weight˜20 g each)were transferred into a 1 L plastic container. Approximately 300 mL(appropriate volume to immerse vials) of 2% HNO₃ solution wastransferred into the container having the vials and placed in an ovenmaintained at 60° C. for ˜24 h. Additionally, the refluxed aqueoussolution (pH 3.4 from the extractable study described above) was alsoanalyzed for metal impurities as metals tend to be extracted more acidicsolutions. Ten elements (Class 1, 2A and 3) were examined. Extracts wereanalyzed by ICP-MS based on USP <233> and following the ICH Q3DPermitted daily exposure (PDE) limits.

Extracts from each reflux solvent were analyzed for extractables usingQTOF LC-MS and GC-MS. Extractables included siloxane oligomers,non-ionic surfactants (Laureth-9 and related), sulfur compounds,Butylated hydroxytoluene (BHT) and fatty acids (mineral fillers)commonly used in the production of elastomeric components. Anotherextractable found in the LC-MS analysis was Triethylene glycol which isa common plasticizer used in vinyl polymers.

Extractable compounds detected in the extracts along with relativequantitation are provided in Tables 29-32. According to themanufacturer, Bisphenol A (BPA), Melamine, 2-Mercaptobenzothiazole,Nitrosamines, Phthalates and Polyvinylchlorides (PVC) are notintentionally added to the stoppers.

TABLE 29 GCMS Extractables Results: 50/50 IPA/Water Extract RT PossibleID Est. Conc. Quantitation (min) Formula Identification CAS Source(μg/mL)* Standard 5.808 N/A Siloxane-related (m/z N/A NIST 0.58 D5 75,77, 103, 117, 119, 161) 6.802 N/A Siloxane-related (m/z N/A NIST 0.16 D575, 77, 103, 117, 119, 161) 8.677 C₈H₂₄O₄Si₄ Octamethyl 556-67-2 NIST0.43 D5 cyclotetrasiloxane (D4) 10.638 C₁₀H₃₀O₅Si₅ Decamethyl 541-02-6NIST 0.18 D5 cyclopentasiloxane (D5) 10.939 N/A Hydrocarbon** N/A NIST1.39 Decane 14.16 C₁₅H₂₄O Butylated 128-37-0 NIST 1.30 BHThydroxytoluene** 14.216 S₆ Cyclohexasulfide 13798-23-7 NIST 0.27Hexadecane 14.454 C₁₂H₂₄0₂ Dodecanoic acid 143-07-7 NIST 0.19 Hexadecane15.686 N/A Hydrocarbon** N/A NIST 4.46 Hexadecane 15.97 C₁₄H₂₈O₂Tetradecanoic acid 544-63-8 NIST 0.13 Hexadecane 17.396 C₁₆H₃₂O₂Hexadecanoic acid 57-10-3 NIST 2.59 Eicosane 18.217 S₈ Sulfur octamer10544-50-0 NIST 0.78 Eicosane 18.662 C₁₈H₃₆O₂ Stearic acid 57-11-4 NIST3.11 Eicosane *Calculated from the average of duplicate injections basedon the calibration equations: Decane, y = 6,247,104.5151x −269,219.0219, R² = 0.9979; D5, y = 16,686,845.9104x + 610,105.5710, R² =0.9961; BHT, y = 20,301,408.1745x − 86,101.7850, R² = 0.9967;Hexadecane, y = 8,934,944.7600x + 59,660.8105, R² = 0.9924; Diisobutylphthalate, y = 14,576,196.4016x − 242,019.4874, R² = 0.9959; Eicosane, y= 7,765,118.6556x − 109,508.8545, R² = 0.9923. **This compound wasquantitated in the 5 × diluted sample extract.

TABLE 30 HPLC-UV-CAD Extractables Results: pH 3.4 Extract RT PositiveNegative Best Possible Est. Conc. Quantitation (min) m/z m/z Mass MatchIdentification (μg/mL)* Standard 1.232 151.0969 150.0897 C₆H₁₄O₄Triethylene glycol <0.5 12-HDA 1.321 166.1232 165.1158 C₁₀H₁₅NOEphedrine** 0.14 Irgacure 184 *Calculated from the average of duplicateinjections based on the calibration equations: Irgacure 184 (UV), y =133.41x + 23.048, R² = 0.9917; 12-HDA (12-Hydroxydodecanoic acid) (CAD),y = 0.019x² − 0.0032x + 0.0866, R² = 1.0000 **This compound isconsidered as a drug related compound, which is unique in the pH 3.4extract compared to the pH 3.4 Control.

TABLE 31 HPLC-UV-CAD Extractables Results: pH 9.4 Extract RT PositiveNegative Best Possible Est. Conc. Quantitation (min) m/z m/z Mass MatchIdentification (μg/mL) * Standard 1.232 151.0969 150.0897 C₆H₁₄O₄Triethylene glycol <0.5 12-HDA 1.746 128.9321 129.9393 H₂O₄S₂ Dithionousacid 3.52 12-HDA 1.831 143.9011 144.9086 HO₃S₃ Thionite related 9.846196.1335 178.0998 C₁₁H₁₄O₂ 1-Hydroxy-1-phenyl- 0.10 Irgacure 1842-pentanone 18.072 440.4109 439.4036 C₂₇H₅₃NO₃ Fatty amide related <0.5Oleamide *Calculated from the average of duplicate injections based onthe calibration equations: Irgacure 184 (UV), y = 133.41x + 23.048, R² =0.9917; 12-HDA (12-Hydroxydodecanoic acid) (CAD), y = 0.019x² −0.0032x + 0.0866, R² = 1.0000; Oleamide (CAD), y = 0.0836x² − 0.4401x +0.3694, R² = 1.0000

TABLE 32 HPLC-UV-CAD Extractables Results: 50/50 IPA/Water Extract Est.RT Positive Negative Possible Conc. Quantitation (min) m/z m/z Mass BestMatch Identification (μg/mL)* Standard 1.113 173.0788 150.0895 C₆H₁₄O₄Triethylene glycol <0.5 12-HDA 5.765 205.1438 204.1365 C₁₀H₂₀O₄Butyldiglycol acetate <0.5 12-HDA 6.883 223.0643 222.0566 C₈H₁₄O₅SLaureth sulfate related <0.5 12-HDA 6.887 275.0362 240.0669 C₈H₁₆O₆SLaureth sulfate related <0.5 12-HDA 7.012 343.2963 342.289 C₁₉H₃₈N₂O₃Lauramidopropyl <0.5 12-HDA betaine 10.905 313.0784 268.0799 C₁₀H₂₀O₄S₂1,8,11,14-Tetraoxa- 4,5- <0.5 12-HDA dithiacyclohexadecane 11.275 N/AN/A N/A N/A UV Unknown 0.41 Irgacure 184 11.672 N/A N/A N/A N/A UVUnknown 0.22 Irgacure 184 13.585 600.468 582.4341 C₃₀H₆₂O₁₀ Laureth-9<0.5 12-HDA 13.847 199.1703 200.1776 C₁₂H₂₄O₂ Lauric acid <0.5 12-HDA13.865 319.2845 318.2804 C₁₈H₃₈O₄ Laureth-3 isomer <0.5 12-HDA 13.893429.319 406.3301 C₂₂H₄₆O₆ Laureth-5 isomer <0.5 12-HDA 13.958 385.2929362.3036 C₂₀H₄₂O₃ Laureth-4 isomer <0.5 12-HDA 14.618 614.4841 596.4501C₃₁H₆₄O₁₀ Laureth-9 related <0.5 12-HDA 14.965 297.2432 298.2507C₁₈H₃₄O₃ Ricinoleic acid <0.5 12-HDA 15.321 429.3191 406.33 C₂₂H₄₆O₆Laureth-5 <0.5 12-HDA 15.393 385.2931 362.3039 C₂₀H₄₂O₃ Laureth-4 <0.512-HDA 15.427 319.2849 318.2779 C₁₈H₃₈O₄ Laureth-3 <0.5 12-HDA 15.461275.2586 274.2513 C₁₆H₃₄O₃ Laureth-2 <0.5 12-HDA 15.913 309.1739 264.174C₁₃H₂₈O₃S Dodecyl 0.65 12-HDA methanesulfonate 15.804 196.1333 178.0995C₁₁H₁₄O₂ 1-Hydroxy-1-phenyl-2- 30.47 Irgacure 184 pentanone 15.924389.1612 390.1685 C₂₂H₃₀O₂S₂ 2,2′-Dithiobis[6-(1,1- dimethylethyl)-4-methylphenol] 16.463 255.233 256.2402 C₁₆H₃₂O₂ Palmitic acid 10.74Oleamide 16.563 227.0749 228.0821 C₁₁H₁₆O₃S 0.25 Irgacure 1845-(tert-Butyl)-3- toluenesulfonic acid 16.845 306.2768 283.2881 C₁₈H₃₇NOStearamide <0.5 Oleamide 16.899 227.2015 228.2088 C₁₄H₂₈O₂ Myristic acid<0.5 Oleamide 16.928 256.2642 255.2569 C₁₆H₃₃NO Palmitamide <0.5Oleamide 17.107 353.2001 354.2074 C₁₆H₃₄O₆S Laureth-2 sulfate <0.5Oleamide 17.86 282.2799 281.2726 C₁₈H₃₅NO Oleamide <0.5 Oleamide*Calculated from the average of duplicate injections based on thecalibration equations: Irgacure 184 (UV), y = 135.71x + 22.797, R² =0.9913; 12-HDA (12-Hydroxydodecanoic acid) (CAD), y =0.0219x² −0.0041x + 0.1085, R² = 1.0000; Oleamide (CAD), y = 0.0944x² − 0.526x +0.5834, R² = 1.0000

To evaluate the metal impurities, the 2% nitric acid stopper extractsand the pH 3.4 reflux extract were screened according to USP <233> basedICP-MS analysis and results are compared against established PDEs of therespective elements. Ten elements (Class 1, 2A and 3) were selected.Results obtained from the ICPMS analysis of the extracting solutionsindicates that the Class 1, 2A and 3 elements were found to be below therespective established PDEs. ICP-MS results from the extractable studyare summarized in Table 33.

TABLE 33 ICP-MS Results for Extractables Study PDE limits ICP-MS ICP-MScalculated based ICP-MS Results Results on 10 mL Results (ppb) (ppb)Parenteral daily max. (ppb) Glass Stoppers Stoppers PDE injection volumevials (2% (2% (Reflux Element Class (μg/day) (ppb)* HNO₃)** HNO₃)** pH3.4)** Cadmium 1 2 200 <2.5 <2.5 <2.5 Lead 1 5 500 <2.5 <2.5 <2.5Arsenic 1 15 1500 <2.5 <2.5 <2.5 Mercury 1 3 300 <2.5 <2.5 <2.5 Cobalt2A 5 500 2.6 <2.5 <2.5 Vanadium 2A 10 1000 <2.5 <2.5 14.5 Nickel 2A 202000 <2.5 <2.5 62.5 Lithium 3 250 25000 2.6 <2.5 <2.5 Antimony 3 90 9000<2.5 <2.5 <2.5 Copper 3 300 30000 3.7 <2.5 <2.5 *PDE value in ppb =Parental PDE value (μg/day) ÷ maximum daily volume (mL/day), i.e., 10mL/day * 1000. **2.5 ppb corresponds to the lowest concentration of therespective element in the calibration curve.

Leachables Study

The three exhibit batches of ready-to-use ephedrine sulfate compositionsof Example 2 stored in an inverted position for 24 months at 25° C.±2°C. and 60%±5% RH were subjected to a leachables study by QTOF GC-MS andLC-MS. A control sample was also prepared in a volumetric flask bydissolving 5 g of Ephedrine Sulfate API and 9 g of NaCl in 1 L purifiedwater. The pH of the resulting solution was ˜5.6.

In the MS study, identification and relative quantitation of leachableswas achieved by GCMS QTOF and LC-MS QTOF analysis. The AnalyticalEvaluation Threshold (AET) was calculated to be 0.15 μg/mL based on themaximum daily dose of the proposed drug product and was set to 0.2 μg/mLin the GC-MS analysis and 0.1 μg/mL in the LC-MS analysis. The drugproduct samples from the three lots described in Example 2 wereextracted as-is and at lower and higher pH to prepare the extracts forGC-MS analysis. The drug product samples were analyzed by LCMS analysiswithout further preparation. The summary of the leachable data forephedrine sulfate injection samples is provided in Table 34, below.Reference Standards of varied structures and chromophores were employedin the MS study and quantitation of extractables and leachables wereperformed based on the calibration curve of closely matched referencestandards.

MS/MS studies were also performed as required to aid identification fromthe fragmentation patterns. It is to be noted that the same test methods(GC-MS and LC-MS) were used for the identification and quantitation ofextractables in the stopper extracts. The extensive list of extractablesof varied structures detected by these methods demonstrate theversatility of these methods. It is evident from the MS data thatnumerous extractables were detected due to the rigorous conditionsemployed in the extractable study, however the only compounds detectedduring the leachable analysis were Dichlorobenzoic acid (1.4 μg/mL orlower) and trace amounts of Bis(2-ethylhexyl) isophthalate (0.15 μg/mLor lower). Results from the leachable identifications and the relativequantitation values are summarized below in Table 34.

TABLE 34 Leachables Identification and Relative Quantitation EstimatedConcentration in Sample (μg/mL) Formula Possible Identification Lot 1Lot 2 Lot 3 C₂₄H₃₈O₄

<0.1 0.15 <0.1 C₇H₄Cl₂O₂

  1.43 1.04 <0.1 *Only one of several possible isomers is shown.

The above-mentioned drug product samples were also analyzed forleachables by a validated HPLC method, EPH-006. EPH-006 was previouslyvalidated in terms of accuracy, precision, linearity and LOQ usingDichlorobenzoic Acid, Diethyl Phthalate (same functional class asBis(2-ethylhexyl) Isophthalate), BPA and an Irganox related leachable.Dichlorobenzoic acid was also detected during the HPLC analysis usingtest method EPH-006 and the results are summarized in Table 35.

TABLE 35 DCBA Quantitation using EPH-006 Lot Amount of DCBA (μg/mL orppm) by EPH-006 1 (Inverted) 0.4 2 (Inverted) 0.7 3 (Inverted) <LOQ(0.1)

The LOQ of the method was determined to be 0.1 ppm which is lower thanthe AET i.e., 0.15 ppm. The only compound detected above the LOQ levelin the drug product samples was 2,4-Dichlorobenzoic acid or its possibleisomer which is consistent with the LC-MS data. It is to be noted thatdichlorobenzoic acid detected both by the MS study and the HPLC analysiswas also detected previously during the leachable analysis of the 18Msamples. Formation of DCBA may be attributed to possible interaction ofbenzoic acid with the chloride ions in the drug product formulation. TheDCBA amount in drug product Lots 1 and 2 (manufactured using same APISiegfried Lot #16152015) is comparatively higher than that of Lot 3(manufactured using different API Siegfried Lot #16152017). Theseresults are in accordance with the previous results and further supportour hypothesis that formation of DCBA may be attributable to interactionof benzoic acid with chloride ions during formulation of theready-to-use ephedrine sulfate compositions consistent with the presentdisclosure.

To evaluate elemental impurities, three exhibit batches of Lots 1-3 ofExample 2 stored in an inverted position for 24M at 25° C.±2° C. and60%±5% RH were analyzed for Class 1 and 2A elements. The ICP-MS data issummarized below in Table 36.

TABLE 36 ICP-MS Results for Ready-to-Use Ephedrine Sulfate CompositionSamples PDE limits calculated ICP- ICP- ICP- Paren- based on MS MS MSteral 10 mL daily Results Results Results PDE max. injection (ppb):(ppb): (ppb): Element Class (μg/day) volume (ppb)* Lot 1 Lot 2 Lot 3Cadmium 1 2 200 <2.5 <2.5 <2.5 Lead 1 5 500 <2.5 <2.5 <2.5 Arsenic 1 151500 <2.5 <2.5 <2.5 Mercury 1 3 300 2.5 <2.5 <2.5 Cobalt 2A 5 500 <2.5<2.5 <2.5 Vanadium 2A 10 1000 <2.5 <2.5 <2.5 Nickel 2A 20 2000 7.0 <2.53.6 *PDE value in ppb = Parental PDE value (μg/day) ÷ maximum dailyvolume (mL/day), i.e., 10 mL/day* 1000.

Conclusion

Extractables and leachables were identified using a combination ofQTOF-GCMS and QTOF-LCMS-UV-CAD. Most of the identified extractables seemto be originating from the elastomeric components or additives. The sametest methods were employed for extractables and leachablesidentification and relative-quantitation with an instrumental analyticalevaluation threshold (AET) set at 0.1 μg/mL for LC-MS analysis and at0.2 μg/mL for GC-MS analysis. During the leachables analysis a compoundconsistent with bis(2-ethylhexyl) isophthalate was detected in EphedrineSulfate Injection samples at a concentration of 0.15 μg/mL or lower byQTOF-GCMS. A compound consistent with dichlorobenzoic acid was detectedin Ephedrine Sulfate Injection samples at a concentration of 1.43 μg/mLor lower by QTOF-LCMS-UV-CAD. Dichlorobenzoic acid was also found inHPLC analysis by EPH-006 with the amounts found at 0.7 μg/mL or lower.Formation of DCBA may be attributed to possible interaction of benzoicacid present in API with the chloride ions in the drug productformulation. Therefore, based on the data from this extractable andleachable study, the safety risk associated with leachables or elementalimpurities in the ready-to-use ephedrine compositions consistent withthe present disclosure appears to be low.

Further Examples

Further Example 1. A composition comprising ephedrine sulfate in water,wherein the ephedrine sulfate is present at a concentration of about 1mg/mL to about 10 mg/mL.

Further Example 2. The composition of Further Example 1, wherein theephedrine sulfate is present at a concentration of about 2 mg/mL toabout 8 mg/mL.

Further Example 3. The composition of Further Example 1, wherein theephedrine sulfate is present at a concentration of about 3 mg/mL toabout 7 mg/mL.

Further Example 4. The composition of Further Example 1, wherein theephedrine sulfate is present at a concentration of about 4 mg/mL toabout 6 mg/mL.

Further Example 5. The composition of Further Example 1, wherein theephedrine sulfate is present at a concentration of about 5 mg/mL.

Further Example 6. The composition of any preceding Further Examplefurther comprising sodium chloride.

Further Example 7. The composition of Further Example 6, wherein thesodium chloride is present in an amount of about 9 mg/mL.

Further Example 8. The composition of any preceding Further Example,wherein the composition is stable when stored at 20° C. under light forat least 12 months.

Further Example 9. The composition of any preceding Further Example,wherein the composition does not include dextrose.

Further Example 10. The composition of any preceding Further Example,wherein the composition does not include benzyl alcohol.

Further Example 11. The composition of any preceding Further Example,wherein the composition consists essentially of ephedrine sulfate,sodium chloride and water.

Further Example 12. The composition of any preceding Further Example,wherein the composition consists of ephedrine sulfate, sodium chlorideand water.

Further Example 13. The composition of any preceding Further Example,wherein the ephedrine sulfate is (−)-ephedrine sulfate.

Further Example 14. A sterile prediluted medicament comprising:

-   -   about 3.8 mg/mL of ephedrine or an equimolar amount of an        ephedrine salt;    -   about 9 mg/mL sodium chloride; and    -   water.

Further Example 15. The sterile prediluted medicament of Further Example14, wherein the medicament does not include dextrose.

Further Example 16. The sterile prediluted medicament of Further Example14 or Further Example 15, wherein the medicament does not include benzylalcohol.

Further Example 17. The sterile prediluted medicament of any one ofFurther Examples 14 to 16, wherein a total volume of the medicament isabout 10 mL.

Further Example 18. The sterile prediluted medicament of any one ofFurther Examples 14 to 17, wherein the medicament is housed in a vial.

Further Example 19. The sterile prediluted medicament of any one ofFurther Examples 14 to 18, wherein after storage at about 20° C. underlight the medicament comprises at least 3 mg/mL of the ephedrine or anmolar equivalent of the ephedrine salt.

Further Example 20. The sterile prediluted medicament of any one ofFurther Examples 14 to 19, wherein the ephedrine or ephedrine salt isephedrine sulfate.

Further Example 21. The sterile prediluted medicament of Further Example20, wherein the ephedrine sulfate is (−)-ephedrine sulfate.

Further Example 22. A ready-to-use unit dose form comprising:

-   -   about 5 mg/mL of ephedrine sulfate;    -   about 9 mg/mL of sodium chloride; and    -   water.

Further Example 23. The ready-to-use unit dose form of Further Example22, wherein the ready-to-use unit dose form is housed in a vial.

Further Example 24. The ready-to-use unit dose form of Further Example22 or Further Example 23, wherein the ready-to-use unit dose form has atotal volume of about 10 mL.

Further Example 25. The ready-to-use unit dose form of any one ofFurther Examples 22 to 24, wherein the ready-to-use unit dose form doesnot include dextrose.

Further Example 26. The ready-to-use unit dose form of any one ofFurther Examples 22 to 25, wherein the ready-to-use unit dose form doesnot include benzyl alcohol.

Further Example 27. The ready-to-use unit dose form of any one ofFurther Examples 22 to 26, wherein after storage at about 20° C. underlight the ready-to-use unit dose form comprises at least 4 mg/mL of theephedrine sulfate.

Further Example 28. A packaged pharmaceutical product comprising:

-   -   a vial; and    -   a solution housed within the vial,    -   wherein the solution comprises, consists essentially of, or        consists of:        -   about 5 mg/mL of ephedrine sulfate;        -   about 9 mg/mL sodium chloride; and        -   water.

Further Example 29. The packaged pharmaceutical product of FurtherExample 28, wherein the solution has a total volume of about 10 mL.

Further Example 30. The packaged pharmaceutical product of FurtherExample 28 or Further Example 29, wherein the solution does not includedextrose.

Further Example 31. The packaged pharmaceutical product of any one ofFurther Examples 28 to 30, wherein the vial comprises, consistsessentially of, or consists of glass.

Further Example 32. The packaged pharmaceutical product of any one ofFurther Examples 28 to 31, wherein the vial comprises, consistsessentially of, or consists of polypropylene.

Further Example 33. The packaged pharmaceutical product of any one ofFurther Examples 28 to 32, wherein the solution is stable when stored atabout 20° C. under light for at least 12 months.

Further Example 34. The packaged pharmaceutical product of FurtherExample 33, wherein after storage at about 20° C. under light for atleast 12 months, the solution comprises ephedrine sulfate at aconcentration of about 4 mg/mL to about 6 mg/mL.

Further Example 35. The packaged pharmaceutical product of FurtherExample 33, wherein after storage at about 20° C. under light for atleast 12 months, the solution comprises at least 4 mg/mL of ephedrinesulfate.

Further Example 36. The packaged pharmaceutical product of FurtherExample 33, wherein after storage at about 20° C. under light for atleast 12 months, the solution comprises at least 4.5 mg/mL ephedrinesulfate.

Further Example 37. The packaged pharmaceutical product of any one ofFurther Examples 28 to 36, wherein the ephedrine sulfate is(−)-ephedrine sulfate.

Further Example 38. A method of administering ephedrine sulfate to asubject in need thereof, the method comprising:

-   -   drawing a composition comprising ephedrine sulfate from a        sterile premixed pharmaceutical product into a syringe; and    -   injecting the composition into the subject using the syringe,    -   wherein the ephedrine sulfate is present in the composition in        an amount of about 5 mg/mL.

Further Example 39. The method of Further Example 38, wherein thecomposition further comprises sodium chloride in an amount of about 9mg/mL.

Further Example 40. The method of Further Example 38 or Further Example39, wherein the composition further comprises water.

Further Example 41. The method of any one of Further Examples 38 to 40,wherein the composition does not include dextrose.

Further Example 42. The method of any one of Further Examples 38 to 41,wherein the method does not include diluting the sterile premixedpharmaceutical product before the step of injecting the composition intothe subject using the syringe.

Further Example 43. The method of any one of Further Examples 38 to 42,wherein the composition housed within the vial of the sterile premixedpharmaceutical product is stable when stored at about 20° C. under lightfor at least 12 months.

Further Example 44. The method of Further Example 43, wherein afterstorage at about 20° C. under light for at least 12 months, thecomposition comprises ephedrine sulfate in an amount of about 4 mg/mL toabout 6 mg/mL.

Further Example 45. The method of any one of Further Examples 38 to 44,wherein the ephedrine sulfate is (−)-ephedrine sulfate.

Further Example 46. A method of making a ready-to-use pharmaceuticalcomposition comprising ephedrine or an ephedrine salt, the methodcomprising:

-   -   combining ephedrine or an ephedrine salt, sodium chloride and        water to provide a solution comprising:    -   about 3.8 mg/mL ephedrine or an equimolar amount of an ephedrine        salt, and    -   about 9 mg/mL sodium chloride; and    -   thereafter sterilizing the solution to provide a ready-to-use        pharmaceutical composition comprising ephedrine or an ephedrine        salt.

Further Example 47. The method of Further Example 46 further comprisingplacing the solution in one or more vials before the step ofsterilizing.

Further Example 48. The method of Further Example 46 or Further Example47, wherein the solution does not include dextrose.

Further Example 49. The method of any one of Further Examples 46 to 48,wherein the pharmaceutical composition is stable when stored at about20° C. under light for at least 12 months.

Further Example 50. The method of Further Example 49, wherein afterstorage at about 20° C. under light for at least 12 months, thepharmaceutical composition comprises an amount of the ephedrine or theephedrine salt that is at least 80% of the about 3.8 mg/mL ephedrine orthe equimolar amount of the ephedrine salt.

Further Example 51. The method of any one of Further Examples 46 to 50,wherein the ephedrine or the ephedrine salt is ephedrine sulfate.

Further Example 52. The method of Further Example 51, wherein theephedrine salt is (−)-ephedrine sulfate.

Further Example 53. The method of Further Example 51 or Further Example52, wherein the equimolar amount of the ephedrine salt is about 5 mg/mLof the ephedrine sulfate.

Further Example 54. The method of any one of Further Examples 46 to 50,wherein the ephedrine or the ephedrine salt is ephedrine hydrochloride.

Further Example 55. The method of Further Example 54, wherein theephedrine hydrochloride is (−)-ephedrine hydrochloride.

Further Example 56. The method of Further Example 54 or Further Example55, wherein the equimolar amount of the ephedrine salt is about 4.6mg/mL of the ephedrine hydrochloride.

Further Example 57. A method of treating hypotension in a subject inneed thereof, the method comprising:

-   -   drawing an effective amount of a packaged composition comprising        ephedrine or an ephedrine salt into a syringe; and    -   injecting the effective amount of the packaged composition into        the subject in need thereof.

Further Example 58. The method of Further Example 57, wherein thepackaged composition comprises ephedrine or an ephedrine salt in anamount equivalent to about 3.8 mg/mL ephedrine.

Further Example 59. The method of Further Example 57 or Further Example58, wherein the packaged composition further comprises sodium chloridein an amount of about 9 mg/mL.

Further Example 60. The method of any one of Further Examples 57 to 59,wherein the packaged composition further comprises water.

Further Example 61. The method of any one of Further Examples 57 to 60,wherein the packaged composition does not include dextrose.

Further Example 62. The method of any one of Further Examples 57 to 61,wherein the method does not include diluting the packaged compositionbefore the step of injecting the effective amount of the packagedcomposition into the subject in need thereof.

Further Example 63. The method of any one of Further Examples 57 to 62,wherein the packaged composition is stable when stored at about 20° C.under light for at least 12 months.

Further Example 64. The method of Further Example 63, wherein afterstorage at about 20° C. under light for at least 12 months, the packagedcomposition comprises ephedrine sulfate in an amount of about 4 mg/mL toabout 6 mg/mL.

Further Example 65. The method of any one of Further Examples 57 to 64,wherein the ephedrine or ephedrine salt is (−)-ephedrine sulfate.

Further Example 66. The method of any one of Further Examples 57 to 65further comprising determining a low blood pressure reading in thesubject before the step of drawing the effective amount of the packagedcomposition comprising ephedrine or an ephedrine salt into the syringe.

Further Example 67. A method of increasing a blood pressure in a subjectin need thereof, the method comprising:

-   -   determining a low blood pressure reading associated with a        subject;    -   drawing about 1 mL to about 10 mL of a packaged composition        comprising about 5.0 mg/mL ephedrine sulfate into a syringe; and    -   injecting about 1 mL to about 10 mL of the packaged composition        into the subject in need thereof,    -   wherein the blood pressure reading associated with the subject        increases after the step of injecting the packaged composition        into the subject in need thereof, and    -   wherein the method does not include diluting the packaged        composition before the step of injecting the packaged        composition into the subject in need thereof.

Further Example 68. The method of Further Example 67, wherein thepackaged composition further comprises sodium chloride in an amount ofabout 9 mg/mL.

Further Example 69. The method of Further Example 67 or Further Example68, wherein the packaged composition further comprises water.

Further Example 70. The method of any one of Further Examples 67 to 69,wherein the packaged composition does not include dextrose.

Further Example 71. The method of any one of Further Examples 67 to 70,wherein the method further comprises determining a second blood pressurereading associated with the subject after the step of injecting thepackaged composition into the subject, wherein the second blood pressurereading is hypotensive.

Further Example 72. The method of Further Example 71 further comprisinginjecting about 1 mL to about 10 mL of the packaged composition into thesubject after the step of determining the second hypotensive bloodpressure reading associated with the subject.

Further Example 73. The method of any one of Further Examples 67 to 72,wherein the packaged composition is stable when stored at about 20° C.under light for at least 12 months.

Further Example 74. The method of Further Example 73, wherein afterstorage at about 20° C. under light for at least 12 months, the packagedcomposition comprises ephedrine sulfate in an amount of at least about 4mg/mL.

Further Example 75. The method of Further Example 73, wherein afterstorage at about 20° C. under light for at least 12 months, the packagedcomposition comprises ephedrine sulfate in an amount of at least about4.5 mg/mL.

Further Example 76. The method of any one of Further Examples 67 to 75,wherein the ephedrine sulfate is (−)-ephedrine sulfate.

Further Example 77. A ready-to-use packaged pharmaceutical compositioncomprising ephedrine or a pharmaceutically acceptable salt thereof,wherein the pharmaceutical composition exhibits no more than about 5%decrease in a concentration of the ephedrine or pharmaceuticallyacceptable salt thereof upon storage for at least 24 months.

Further Example 78. The ready-to-use packaged pharmaceutical compositionof Further Example 77 further comprising sodium chloride.

Further Example 79. The ready-to-use packaged pharmaceutical compositionof Further Example 77 or 78, wherein the ready-to-use packagedpharmaceutical composition is stored in a sealed glass container.

Further Example 80. The ready-to-use packaged pharmaceutical compositionof any one of Further Examples 77-79, wherein the composition does notinclude dextrose.

Further Example 81. The ready-to-use packaged pharmaceutical compositionof any one of

Further Examples 77-80, wherein the composition does not include benzylalcohol.

Further Example 82. The ready-to-use packaged pharmaceutical compositionof any one of Further Examples 77-81, wherein the composition consistsessentially of ephedrine or a pharmaceutically acceptable salt thereof,sodium chloride and water.

Further Example 83. The ready-to-use packaged pharmaceutical compositionof any one of

Further Examples 77-82 comprising about 5 mg/mL ephedrine sulfate.

Further Example 84. The ready-to-use packaged pharmaceutical compositionof any one of Further Examples 77-82 comprising about 3.8 mg/mLephedrine base.

Further Example 85. The ready-to-use packaged pharmaceutical compositionof any one of Further Examples 77-84, wherein the ephedrine sulfate is(−)-ephedrine sulfate.

Further Example 86. The ready-to-use packaged pharmaceutical compositionof any one of Further Examples 77-85, wherein the composition isformulated as a total volume of about 10 mL.

CONCLUSION

Unless otherwise specified or required by context, the term “ephedrine”as used herein refers to (−)-ephedrine (i.e.,(1R,2S)-2-methylamino-1-phenylpropan-1-ol sulfate).

The foregoing descriptions of specific embodiments of the presentinvention have been presented for purposes of illustration anddescription. They are not intended to be exhaustive or to limit theinvention to the precise forms disclosed, and obviously manymodifications and variations are possible in light of the aboveteaching. The embodiments were chosen and described in order to bestexplain the principles of the invention and its practical application,to thereby enable others skilled in the art to best utilize theinvention and various embodiments with various modifications as aresuited to the particular use contemplated. It is intended that the scopeof the invention be defined by the Claims appended hereto and theirequivalents.

It is to be understood that both the foregoing descriptions areexemplary and explanatory only, and are not restrictive of the methodsand devices described herein. In this application, the use of thesingular includes the plural unless specifically stated otherwise. Also,the use of “or” means “and/or” unless stated otherwise. Similarly,“comprise,” “comprises,” “comprising,” “include,” “includes” and“including” are not intended to be limiting.

All patents, patent applications, publications, and references citedherein are expressly incorporated by reference to the same extent as ifeach individual publication or patent application was specifically andindividually indicated to be incorporated by reference.

What is claimed is:
 1. A method of administering ephedrine sulfate to asubject having hypotension or an elevated risk of developing hypotensionin need thereof, the method consisting essentially of: drawing ashelf-stable ready-to-use ephedrine sulfate composition from a sterilepremixed pharmaceutical product into a syringe; and injecting thecomposition into the subject using the syringe, wherein the shelf-stableready-to-use ephedrine sulfate composition consists essentially of: 5mg/mL+/−5% ephedrine sulfate; 9 mg/mL sodium chloride; no preservative;and water, and wherein the shelf-stable ready-to-use ephedrine sulfatecomposition is prepared by a process comprising: combining ephedrinesulfate, sodium chloride, and water to form a solution comprising 5mg/mL+/−5% of ephedrine sulfate and 9 mg/mL sodium chloride; filteringthe solution comprising 5 mg/mL+/−5% of ephedrine sulfate and 9 mg/mLsodium chloride; placing the filtered solution into depyrogenated glassvials; and sealing the filled glass vials.
 2. The method of claim 1,wherein the step of sealing the filled glass vials comprises sealing thefilled glass vials with coated rubber stoppers.
 3. The method of claim1, wherein a pH level of the shelf-stable ready-to-use ephedrine sulfatecomposition is within 0.5 pH units of an initial pH level after storageat 25° C. and 60% relative humidity for 12 months.
 4. The method ofclaim 1, wherein a pH level of the shelf-stable ready-to-use ephedrinesulfate composition is within 0.5 pH units of an initial pH level afterstorage at 40° C. and 75% relative humidity for 6 months.
 5. The methodof claim 1, wherein the shelf-stable ready-to-use ephedrine sulfatecomposition has an initial pH level of about 4.5 to about
 7. 6. A methodof administering ephedrine sulfate to a subject having hypotension or anelevated risk of developing hypotension in need thereof, the methodcomprising: drawing a sterile, shelf-stable ready-to-use ephedrinesulfate pharmaceutical product comprising 5 mg/mL+/−5% ephedrine sulfateand no preservative from a sealed glass vial into a syringe; andinjecting the composition into the subject using the syringe, whereinthe sterile, shelf-stable ready-to-use ephedrine sulfate pharmaceuticalproduct is prepared by a process comprising: combining ephedrinesulfate, sodium chloride, and water to form a solution consistingessentially of 5 mg/mL+/−5% of ephedrine sulfate and 9 mg/mL sodiumchloride and having an initial pH level; thereafter filtering thesolution through a membrane filter to form a filtered solution;thereafter placing the filtered solution into depyrogenated glass vials;and sealing the filled glass vials.
 7. The method of claim 6, whereinthe step of sealing the filled glass vials comprises sealing the filledglass vials with coated rubber stoppers.
 8. The method of claim 6,wherein the initial pH level is about 4.5 to about
 7. 9. The method ofclaim 8, wherein a pH level of the shelf-stable ready-to-use ephedrinesulfate composition is within 0.5 pH units of the initial pH level afterstorage at 25° C. and 60% relative humidity for 12 months.
 10. Themethod of claim 8, wherein a pH level of the shelf-stable ready-to-useephedrine sulfate composition is within 0.5 pH units of the initial pHlevel after storage at 40° C. and 75% relative humidity for 6 months.11. A method of administering ephedrine sulfate to a subject havinghypotension or an elevated risk of developing hypotension in needthereof, the method comprising: drawing a shelf-stable ready-to-useephedrine sulfate composition from a sterile premixed pharmaceuticalproduct into a syringe; and injecting the composition into the subjectusing the syringe, wherein the shelf-stable ready-to-use ephedrinesulfate composition consists essentially of: 5 mg/mL ephedrine sulfate;9 mg/mL sodium chloride; no preservative; and water, and wherein theshelf-stable ready-to-use ephedrine sulfate composition is prepared by aprocess comprising: combining ephedrine sulfate, sodium chloride, andwater to form a solution comprising 5 mg/mL of ephedrine sulfate and 9mg/mL sodium chloride; placing the solution into glass vials to formfilled glass vials; and sealing the filled glass vials.
 12. The methodof claim 11, wherein the step of sealing the filled glass vialscomprises sealing the filled glass vials with coated rubber stoppers.13. The method of claim 11, wherein the shelf-stable ready-to-useephedrine sulfate composition has an initial pH level of about 4.5 toabout
 7. 14. The method of claim 13, wherein a pH level of theshelf-stable ready-to-use ephedrine sulfate composition is within 0.5 pHunits of the initial pH level after storage at 25° C. and 60% relativehumidity for 12 months.
 15. The method of claim 13, wherein a pH levelof the shelf-stable ready-to-use ephedrine sulfate composition is within0.5 pH units of the initial pH level after storage at 40° C. and 75%relative humidity for 6 months.